Full text data of IRAK4
IRAK4
[Confidence: low (only semi-automatic identification from reviews)]
Interleukin-1 receptor-associated kinase 4; IRAK-4; 2.7.11.1 (Renal carcinoma antigen NY-REN-64)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Interleukin-1 receptor-associated kinase 4; IRAK-4; 2.7.11.1 (Renal carcinoma antigen NY-REN-64)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9NWZ3
ID IRAK4_HUMAN Reviewed; 460 AA.
AC Q9NWZ3; Q69FE1; Q8TDF7; Q9Y589;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2000, sequence version 1.
DT 22-JAN-2014, entry version 130.
DE RecName: Full=Interleukin-1 receptor-associated kinase 4;
DE Short=IRAK-4;
DE EC=2.7.11.1;
DE AltName: Full=Renal carcinoma antigen NY-REN-64;
GN Name=IRAK4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND INTERACTION WITH
RP IRAK1 AND TRAF6.
RX PubMed=11960013; DOI=10.1073/pnas.082100399;
RA Li S., Strelow A., Fontana E.J., Wesche H.;
RT "IRAK4: a novel member of the IRAK family with the properties of an
RT IRAK-kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:5567-5572(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND IDENTIFICATION AS A RENAL
RP CANCER ANTIGEN.
RX PubMed=10508479;
RX DOI=10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5;
RA Scanlan M.J., Gordan J.D., Williamson B., Stockert E., Bander N.H.,
RA Jongeneel C.V., Gure A.O., Jaeger D., Jaeger E., Knuth A., Chen Y.-T.,
RA Old L.J.;
RT "Antigens recognized by autologous antibody in patients with renal-
RT cell carcinoma.";
RL Int. J. Cancer 83:456-464(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Spleen;
RA Chuang T.H., Ulevitch R.J.;
RT "Human interleukin-1 receptor associated kinase 4 cDNA sequences.";
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-98; ARG-390 AND
RP THR-428.
RG SeattleSNPs variation discovery resource;
RL Submitted (NOV-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP INTERACTION WITH IRAK1; PELI1 AND TRAF6.
RX PubMed=12496252; DOI=10.1074/jbc.M212112200;
RA Jiang Z., Johnson H.J., Nie H., Qin J., Bird T.A., Li X.;
RT "Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling
RT through its interaction with the IL-1 receptor-associated kinase 4
RT (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6
RT (TRAF6) complex.";
RL J. Biol. Chem. 278:10952-10956(2003).
RN [9]
RP FUNCTION IN PHOSPHORYLATION OF IRAK1.
RX PubMed=12538665; DOI=10.1084/jem.20021790;
RA Burns K., Janssens S., Brissoni B., Olivos N., Beyaert R., Tschopp J.;
RT "Inhibition of interleukin 1 receptor/Toll-like receptor signaling
RT through the alternatively spliced, short form of MyD88 is due to its
RT failure to recruit IRAK-4.";
RL J. Exp. Med. 197:263-268(2003).
RN [10]
RP INVOLVEMENT IN IRAK4D.
RX PubMed=12925671; DOI=10.1084/jem.20030701;
RA Medvedev A.E., Lentschat A., Kuhns D.B., Blanco J.C.G., Salkowski C.,
RA Zhang S., Arditi M., Gallin J.I., Vogel S.N.;
RT "Distinct mutations in IRAK-4 confer hyporesponsiveness to
RT lipopolysaccharide and interleukin-1 in a patient with recurrent
RT bacterial infections.";
RL J. Exp. Med. 198:521-531(2003).
RN [11]
RP FUNCTION, AND MUTAGENESIS OF LYS-213.
RX PubMed=15084582; DOI=10.1074/jbc.M400785200;
RA Qin J., Jiang Z., Qian Y., Casanova J.-L., Li X.;
RT "IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-
RT associated kinase phosphorylation and IL-1 responsiveness.";
RL J. Biol. Chem. 279:26748-26753(2004).
RN [12]
RP INVOLVEMENT IN IRAK4D.
RX PubMed=12637671; DOI=10.1126/science.1081902;
RA Picard C., Puel A., Bonnet M., Ku C.-L., Bustamante J., Yang K.,
RA Soudais C., Dupuis S., Feinberg J., Fieschi C., Elbim C.,
RA Hitchcock R., Lammas D., Davies G., Al-Ghonaium A., Al-Rayes H.,
RA Al-Jumaah S., Al-Hajjar S., Al-Mohsen I.Z., Frayha H.H., Rucker R.,
RA Hawn T.R., Aderem A., Tufenkeji H., Haraguchi S., Day N.K., Good R.A.,
RA Gougerot-Pocidalo M.-A., Ozinsky A., Casanova J.-L.;
RT "Pyogenic bacterial infections in humans with IRAK-4 deficiency.";
RL Science 299:2076-2079(2003).
RN [13]
RP INTERACTION WITH IL1RL1.
RX PubMed=16286016; DOI=10.1016/j.immuni.2005.09.015;
RA Schmitz J., Owyang A., Oldham E., Song Y., Murphy E., McClanahan T.K.,
RA Zurawski G., Moshrefi M., Qin J., Li X., Gorman D.M., Bazan J.F.,
RA Kastelein R.A.;
RT "IL-33, an interleukin-1-like cytokine that signals via the IL-1
RT receptor-related protein ST 2 and induces T helper type 2-associated
RT cytokines.";
RL Immunity 23:479-490(2005).
RN [14]
RP IDENTIFICATION IN COMPLEX WITH IRAK1; MYD88; PELI1 AND TRAF6.
RX PubMed=16951688; DOI=10.1038/ni1383;
RA Choi K.C., Lee Y.S., Lim S., Choi H.K., Lee C.H., Lee E.K., Hong S.,
RA Kim I.H., Kim S.J., Park S.H.;
RT "Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor
RT signaling through direct interaction with the adaptor Pellino-1.";
RL Nat. Immunol. 7:1057-1065(2006).
RN [15]
RP FUNCTION IN PHOSPHORYLATION OF NCF1.
RX PubMed=17217339; DOI=10.1042/BJ20061184;
RA Pacquelet S., Johnson J.L., Ellis B.A., Brzezinska A.A., Lane W.S.,
RA Munafo D.B., Catz S.D.;
RT "Cross-talk between IRAK-4 and the NADPH oxidase.";
RL Biochem. J. 403:451-461(2007).
RN [16]
RP FUNCTION IN TLR7 SIGNALING PATHWAY.
RX PubMed=17337443; DOI=10.1074/jbc.M700548200;
RA Koziczak-Holbro M., Joyce C., Gluck A., Kinzel B., Muller M.,
RA Tschopp C., Mathison J.C., Davis C.N., Gram H.;
RT "IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor-
RT and toll-like receptor 7-mediated signaling and gene expression.";
RL J. Biol. Chem. 282:13552-13560(2007).
RN [17]
RP INVOLVEMENT IN IPD1.
RX PubMed=16950813; DOI=10.1136/jmg.2006.044446;
RA Ku C.-L., Picard C., Erdos M., Jeurissen A., Bustamante J., Puel A.,
RA von Bernuth H., Filipe-Santos O., Chang H.-H., Lawrence T., Raes M.,
RA Marodi L., Bossuyt X., Casanova J.-L.;
RT "IRAK4 and NEMO mutations in otherwise healthy children with recurrent
RT invasive pneumococcal disease.";
RL J. Med. Genet. 44:16-23(2007).
RN [18]
RP FUNCTION IN PHOSPHORYLATION OF PELI1.
RX PubMed=17997719; DOI=10.1042/BJ20071365;
RA Ordureau A., Smith H., Windheim M., Peggie M., Carrick E., Morrice N.,
RA Cohen P.;
RT "The IRAK-catalysed activation of the E3 ligase function of Pellino
RT isoforms induces the Lys63-linked polyubiquitination of IRAK1.";
RL Biochem. J. 409:43-52(2008).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [22]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-34, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [23]
RP FUNCTION IN PHOSPHORYLATION OF TIRAP.
RX PubMed=20400509; DOI=10.1074/jbc.M109.098137;
RA Dunne A., Carpenter S., Brikos C., Gray P., Strelow A., Wesche H.,
RA Morrice N., O'Neill L.A.;
RT "IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and
RT degradation of MyD88 adaptor-like (Mal).";
RL J. Biol. Chem. 285:18276-18282(2010).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [26]
RP SUBCELLULAR LOCATION.
RX PubMed=21325272; DOI=10.1074/jbc.M110.199653;
RA Nagpal K., Plantinga T.S., Sirois C.M., Monks B.G., Latz E.,
RA Netea M.G., Golenbock D.T.;
RT "Natural loss-of-function mutation of myeloid differentiation protein
RT 88 disrupts its ability to form Myddosomes.";
RL J. Biol. Chem. 286:11875-11882(2011).
RN [27]
RP REVIEW ON MYDDOSOME.
RX PubMed=21269878; DOI=10.1016/j.it.2010.12.005;
RA Gay N.J., Gangloff M., O'Neill L.A.;
RT "What the Myddosome structure tells us about the initiation of innate
RT immunity.";
RL Trends Immunol. 32:104-109(2011).
RN [28]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 154-460 IN COMPLEX WITH
RP INHIBITORS, AND PHOSPHORYLATION AT THR-345 AND SER-346.
RX PubMed=17161373; DOI=10.1016/j.str.2006.11.001;
RA Wang Z., Liu J., Sudom A., Ayres M., Li S., Wesche H., Powers J.P.,
RA Walker N.P.C.;
RT "Crystal structures of IRAK-4 kinase in complex with inhibitors: a
RT serine/threonine kinase with tyrosine as a gatekeeper.";
RL Structure 14:1835-1844(2006).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 163-460, AND PHOSPHORYLATION
RP AT THR-342 AND THR-345.
RA Mol C.D., Arduini R.M., Baker D.P., Chien E.Y., Dougan D.R.,
RA Friedman J., Gibaja V., Hession C.A., Horne A.;
RT "Crystal structures of the apo and inhibited IRAK4 kinase domain.";
RL Submitted (DEC-2006) to the PDB data bank.
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 160-460 IN COMPLEX WITH ATP
RP ANALOGS, PHOSPHORYLATION AT THR-342; THR-345 AND SER-346, AND
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=17312103;
RA Kuglstatter A., Villasenor A.G., Shaw D., Lee S.W., Tsing S., Niu L.,
RA Song K.W., Barnett J.W., Browner M.F.;
RT "Cutting Edge: IL-1 receptor-associated kinase 4 structures reveal
RT novel features and multiple conformations.";
RL J. Immunol. 178:2641-2645(2007).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (3.40 ANGSTROMS) OF 4-106.
RX PubMed=20485341; DOI=10.1038/nature09121;
RA Lin S.-C., Lo Y.-C., Wu H.;
RT "Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R
RT signalling.";
RL Nature 465:885-890(2010).
RN [33]
RP VARIANTS [LARGE SCALE ANALYSIS] VAL-5; VAL-355; HIS-391 AND THR-428.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine-protein kinase that plays a critical
CC role in initiating innate immune response against foreign
CC pathogens. Involved in Toll-like receptor (TLR) and IL-1R
CC signaling pathways. Is rapidly recruited by MYD88 to the receptor-
CC signaling complex upon TLR activation to form the Myddosome
CC together with IRAK2. Phosphorylates initially IRAK1, thus
CC stimulating the kinase activity and intensive autophosphorylation
CC of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins
CC (PELI1, PELI2 and PELI3) to promote pellino-mediated
CC polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of
CC IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the
CC IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In
CC turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB)
CC leading to NF-kappa-B nuclear translocation and activation.
CC Alternatively, phosphorylates TIRAP to promote its ubiquitination
CC and subsequent degradation. Phosphorylates NCF1 and regulates
CC NADPH oxidase activation after LPS stimulation suggesting a
CC similar mechanism during microbial infections.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=650 uM for ATP (at pH 7.5);
CC KM=1100 uM for substrate (at pH 7.5);
CC -!- SUBUNIT: Associates with MYD88 and IRAK2 to form a ternary complex
CC called the Myddosome. Once phosphorylated, IRAK4 dissociates from
CC the receptor complex and then associates with the TNF receptor-
CC associated factor 6 (TRAF6), IRAK1, and PELI1; this intermediate
CC complex is required for subsequent NF-kappa-B activation. Direct
CC binding of SMAD6 to PELI1 prevents complex formation and hence
CC negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-
CC mediated gene expression. Interacts with IL1RL1.
CC -!- INTERACTION:
CC Q9HAT8:PELI2; NbExp=3; IntAct=EBI-448378, EBI-448407;
CC P58753:TIRAP; NbExp=2; IntAct=EBI-448378, EBI-528644;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9NWZ3-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NWZ3-2; Sequence=VSP_041556;
CC -!- PTM: Phosphorylated (By similarity).
CC -!- DISEASE: Recurrent isolated invasive pneumococcal disease 1 (IPD1)
CC [MIM:610799]: Recurrent invasive pneumococcal disease (IPD) is
CC defined as two episodes of IPD occurring at least 1 month apart,
CC whether caused by the same or different serotypes or strains.
CC Recurrent IPD occurs in at least 2% of patients in most series,
CC making IPD the most important known risk factor for subsequent
CC IPD. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: IRAK4 deficiency (IRAK4D) [MIM:607676]: Causes
CC extracellular pyogenic bacterial and fungal infections in
CC otherwise healthy children. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. Pelle subfamily.
CC -!- SIMILARITY: Contains 1 death domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=IRAK4base; Note=IRAK4 mutation db;
CC URL="http://bioinf.uta.fi/IRAK4base/";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/irak4/";
CC -----------------------------------------------------------------------
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DR EMBL; AF445802; AAM15772.1; -; mRNA.
DR EMBL; AF155118; AAD42884.1; -; mRNA.
DR EMBL; AY340964; AAR02360.1; -; mRNA.
DR EMBL; AY340965; AAR02361.1; -; mRNA.
DR EMBL; AY340966; AAR02362.1; -; mRNA.
DR EMBL; AY340967; AAR02363.1; -; mRNA.
DR EMBL; AK000528; BAA91232.1; -; mRNA.
DR EMBL; AK299944; BAG61774.1; -; mRNA.
DR EMBL; AY186092; AAN75440.1; -; Genomic_DNA.
DR EMBL; AC093012; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC013316; AAH13316.1; -; mRNA.
DR RefSeq; NP_001107654.1; NM_001114182.2.
DR RefSeq; NP_001138728.1; NM_001145256.1.
DR RefSeq; NP_001138729.1; NM_001145257.1.
DR RefSeq; NP_001138730.1; NM_001145258.1.
DR RefSeq; NP_057207.2; NM_016123.3.
DR RefSeq; XP_005269000.1; XM_005268943.1.
DR RefSeq; XP_005269001.1; XM_005268944.1.
DR RefSeq; XP_005269002.1; XM_005268945.1.
DR RefSeq; XP_005269003.1; XM_005268946.1.
DR RefSeq; XP_005269004.1; XM_005268947.1.
DR RefSeq; XP_005269005.1; XM_005268948.1.
DR RefSeq; XP_005269006.1; XM_005268949.1.
DR UniGene; Hs.138499; -.
DR PDB; 2NRU; X-ray; 2.00 A; A/B/C/D=154-460.
DR PDB; 2NRY; X-ray; 2.15 A; A/B/C/D=154-460.
DR PDB; 2O8Y; X-ray; 2.40 A; A/B=163-460.
DR PDB; 2OIB; X-ray; 2.00 A; A/B/C/D=160-460.
DR PDB; 2OIC; X-ray; 2.40 A; A/B/C/D=160-460.
DR PDB; 2OID; X-ray; 2.30 A; A/B/C/D=160-460.
DR PDB; 3MOP; X-ray; 3.40 A; G/H/I/J=4-106.
DR PDBsum; 2NRU; -.
DR PDBsum; 2NRY; -.
DR PDBsum; 2O8Y; -.
DR PDBsum; 2OIB; -.
DR PDBsum; 2OIC; -.
DR PDBsum; 2OID; -.
DR PDBsum; 3MOP; -.
DR ProteinModelPortal; Q9NWZ3; -.
DR SMR; Q9NWZ3; 4-458.
DR DIP; DIP-31351N; -.
DR IntAct; Q9NWZ3; 10.
DR MINT; MINT-1383671; -.
DR STRING; 9606.ENSP00000349096; -.
DR BindingDB; Q9NWZ3; -.
DR ChEMBL; CHEMBL3778; -.
DR GuidetoPHARMACOLOGY; 2045; -.
DR DMDM; 50401181; -.
DR PaxDb; Q9NWZ3; -.
DR PRIDE; Q9NWZ3; -.
DR DNASU; 51135; -.
DR Ensembl; ENST00000431837; ENSP00000390327; ENSG00000198001.
DR Ensembl; ENST00000440781; ENSP00000408734; ENSG00000198001.
DR Ensembl; ENST00000448290; ENSP00000390651; ENSG00000198001.
DR Ensembl; ENST00000551736; ENSP00000446490; ENSG00000198001.
DR GeneID; 51135; -.
DR KEGG; hsa:51135; -.
DR UCSC; uc001rnt.3; human.
DR CTD; 51135; -.
DR GeneCards; GC12P044152; -.
DR HGNC; HGNC:17967; IRAK4.
DR HPA; CAB016685; -.
DR HPA; CAB022077; -.
DR HPA; HPA000924; -.
DR MIM; 606883; gene.
DR MIM; 607676; phenotype.
DR MIM; 610799; phenotype.
DR neXtProt; NX_Q9NWZ3; -.
DR Orphanet; 70592; Immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency.
DR PharmGKB; PA134914577; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000116550; -.
DR HOVERGEN; HBG066836; -.
DR InParanoid; Q9NWZ3; -.
DR KO; K04733; -.
DR OMA; YMPPDSS; -.
DR OrthoDB; EOG7MD4Q1; -.
DR PhylomeDB; Q9NWZ3; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q9NWZ3; -.
DR EvolutionaryTrace; Q9NWZ3; -.
DR GenomeRNAi; 51135; -.
DR NextBio; 53983; -.
DR PRO; PR:Q9NWZ3; -.
DR ArrayExpress; Q9NWZ3; -.
DR Bgee; Q9NWZ3; -.
DR CleanEx; HS_IRAK4; -.
DR Genevestigator; Q9NWZ3; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; EXP:Reactome.
DR GO; GO:0001816; P:cytokine production; IEA:Ensembl.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:UniProtKB.
DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:UniProtKB.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR011029; DEATH-like_dom.
DR InterPro; IPR017428; IL-1_rcpt-assoc_kin4.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR Pfam; PF00069; Pkinase; 1.
DR PIRSF; PIRSF038189; IRAK4; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50017; DEATH_DOMAIN; FALSE_NEG.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; FALSE_NEG.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding;
KW Complete proteome; Cytoplasm; Immunity; Innate immunity; Kinase;
KW Magnesium; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Reference proteome; Serine/threonine-protein kinase; Transferase.
FT CHAIN 1 460 Interleukin-1 receptor-associated kinase
FT 4.
FT /FTId=PRO_0000086035.
FT DOMAIN 20 104 Death.
FT DOMAIN 186 454 Protein kinase.
FT NP_BIND 192 200 ATP (By similarity).
FT NP_BIND 313 316 ATP.
FT ACT_SITE 311 311 Proton acceptor (By similarity).
FT BINDING 213 213 ATP.
FT BINDING 329 329 ATP.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 34 34 N6-acetyllysine.
FT MOD_RES 342 342 Phosphothreonine.
FT MOD_RES 345 345 Phosphothreonine.
FT MOD_RES 346 346 Phosphoserine.
FT VAR_SEQ 1 124 Missing (in isoform 2).
FT /FTId=VSP_041556.
FT VARIANT 5 5 I -> V (in dbSNP:rs56312115).
FT /FTId=VAR_040588.
FT VARIANT 98 98 S -> R (in dbSNP:rs4251469).
FT /FTId=VAR_019354.
FT VARIANT 355 355 M -> V.
FT /FTId=VAR_040589.
FT VARIANT 390 390 H -> R (in dbSNP:rs4251583).
FT /FTId=VAR_019355.
FT VARIANT 391 391 R -> H (in dbSNP:rs55944915).
FT /FTId=VAR_040590.
FT VARIANT 428 428 A -> T (in dbSNP:rs4251545).
FT /FTId=VAR_019356.
FT MUTAGEN 213 213 K->A: Loss of kinase activity.
FT CONFLICT 81 81 V -> A (in Ref. 1; AAM15772).
FT CONFLICT 432 432 V -> G (in Ref. 2; AAD42884).
FT CONFLICT 437 437 L -> R (in Ref. 2; AAD42884).
FT CONFLICT 444 444 R -> S (in Ref. 2; AAD42884).
FT CONFLICT 451 451 Q -> H (in Ref. 2; AAD42884).
FT HELIX 11 13
FT HELIX 16 26
FT HELIX 31 38
FT STRAND 42 48
FT HELIX 50 57
FT HELIX 58 60
FT TURN 61 63
FT HELIX 66 73
FT TURN 74 77
FT HELIX 81 89
FT TURN 90 92
FT HELIX 94 100
FT STRAND 102 104
FT STRAND 166 168
FT HELIX 170 176
FT TURN 177 180
FT TURN 185 188
FT STRAND 191 194
FT STRAND 196 207
FT STRAND 209 215
FT TURN 223 225
FT HELIX 226 239
FT STRAND 248 252
FT STRAND 254 257
FT STRAND 259 263
FT HELIX 270 275
FT HELIX 277 279
FT HELIX 285 304
FT HELIX 314 316
FT STRAND 317 319
FT STRAND 325 327
FT HELIX 352 354
FT HELIX 357 360
FT HELIX 367 382
FT STRAND 391 395
FT HELIX 398 404
FT HELIX 410 413
FT HELIX 423 436
FT TURN 441 443
FT HELIX 447 457
SQ SEQUENCE 460 AA; 51530 MW; 6C8156ADF25FF81E CRC64;
MNKPITPSTY VRCLNVGLIR KLSDFIDPQE GWKKLAVAIK KPSGDDRYNQ FHIRRFEALL
QTGKSPTSEL LFDWGTTNCT VGDLVDLLIQ NEFFAPASLL LPDAVPKTAN TLPSKEAITV
QQKQMPFCDK DRTLMTPVQN LEQSYMPPDS SSPENKSLEV SDTRFHSFSF YELKNVTNNF
DERPISVGGN KMGEGGFGVV YKGYVNNTTV AVKKLAAMVD ITTEELKQQF DQEIKVMAKC
QHENLVELLG FSSDGDDLCL VYVYMPNGSL LDRLSCLDGT PPLSWHMRCK IAQGAANGIN
FLHENHHIHR DIKSANILLD EAFTAKISDF GLARASEKFA QTVMTSRIVG TTAYMAPEAL
RGEITPKSDI YSFGVVLLEI ITGLPAVDEH REPQLLLDIK EEIEDEEKTI EDYIDKKMND
ADSTSVEAMY SVASQCLHEK KNKRPDIKKV QQLLQEMTAS
//
ID IRAK4_HUMAN Reviewed; 460 AA.
AC Q9NWZ3; Q69FE1; Q8TDF7; Q9Y589;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2000, sequence version 1.
DT 22-JAN-2014, entry version 130.
DE RecName: Full=Interleukin-1 receptor-associated kinase 4;
DE Short=IRAK-4;
DE EC=2.7.11.1;
DE AltName: Full=Renal carcinoma antigen NY-REN-64;
GN Name=IRAK4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND INTERACTION WITH
RP IRAK1 AND TRAF6.
RX PubMed=11960013; DOI=10.1073/pnas.082100399;
RA Li S., Strelow A., Fontana E.J., Wesche H.;
RT "IRAK4: a novel member of the IRAK family with the properties of an
RT IRAK-kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:5567-5572(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND IDENTIFICATION AS A RENAL
RP CANCER ANTIGEN.
RX PubMed=10508479;
RX DOI=10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5;
RA Scanlan M.J., Gordan J.D., Williamson B., Stockert E., Bander N.H.,
RA Jongeneel C.V., Gure A.O., Jaeger D., Jaeger E., Knuth A., Chen Y.-T.,
RA Old L.J.;
RT "Antigens recognized by autologous antibody in patients with renal-
RT cell carcinoma.";
RL Int. J. Cancer 83:456-464(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Spleen;
RA Chuang T.H., Ulevitch R.J.;
RT "Human interleukin-1 receptor associated kinase 4 cDNA sequences.";
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-98; ARG-390 AND
RP THR-428.
RG SeattleSNPs variation discovery resource;
RL Submitted (NOV-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP INTERACTION WITH IRAK1; PELI1 AND TRAF6.
RX PubMed=12496252; DOI=10.1074/jbc.M212112200;
RA Jiang Z., Johnson H.J., Nie H., Qin J., Bird T.A., Li X.;
RT "Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling
RT through its interaction with the IL-1 receptor-associated kinase 4
RT (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6
RT (TRAF6) complex.";
RL J. Biol. Chem. 278:10952-10956(2003).
RN [9]
RP FUNCTION IN PHOSPHORYLATION OF IRAK1.
RX PubMed=12538665; DOI=10.1084/jem.20021790;
RA Burns K., Janssens S., Brissoni B., Olivos N., Beyaert R., Tschopp J.;
RT "Inhibition of interleukin 1 receptor/Toll-like receptor signaling
RT through the alternatively spliced, short form of MyD88 is due to its
RT failure to recruit IRAK-4.";
RL J. Exp. Med. 197:263-268(2003).
RN [10]
RP INVOLVEMENT IN IRAK4D.
RX PubMed=12925671; DOI=10.1084/jem.20030701;
RA Medvedev A.E., Lentschat A., Kuhns D.B., Blanco J.C.G., Salkowski C.,
RA Zhang S., Arditi M., Gallin J.I., Vogel S.N.;
RT "Distinct mutations in IRAK-4 confer hyporesponsiveness to
RT lipopolysaccharide and interleukin-1 in a patient with recurrent
RT bacterial infections.";
RL J. Exp. Med. 198:521-531(2003).
RN [11]
RP FUNCTION, AND MUTAGENESIS OF LYS-213.
RX PubMed=15084582; DOI=10.1074/jbc.M400785200;
RA Qin J., Jiang Z., Qian Y., Casanova J.-L., Li X.;
RT "IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-
RT associated kinase phosphorylation and IL-1 responsiveness.";
RL J. Biol. Chem. 279:26748-26753(2004).
RN [12]
RP INVOLVEMENT IN IRAK4D.
RX PubMed=12637671; DOI=10.1126/science.1081902;
RA Picard C., Puel A., Bonnet M., Ku C.-L., Bustamante J., Yang K.,
RA Soudais C., Dupuis S., Feinberg J., Fieschi C., Elbim C.,
RA Hitchcock R., Lammas D., Davies G., Al-Ghonaium A., Al-Rayes H.,
RA Al-Jumaah S., Al-Hajjar S., Al-Mohsen I.Z., Frayha H.H., Rucker R.,
RA Hawn T.R., Aderem A., Tufenkeji H., Haraguchi S., Day N.K., Good R.A.,
RA Gougerot-Pocidalo M.-A., Ozinsky A., Casanova J.-L.;
RT "Pyogenic bacterial infections in humans with IRAK-4 deficiency.";
RL Science 299:2076-2079(2003).
RN [13]
RP INTERACTION WITH IL1RL1.
RX PubMed=16286016; DOI=10.1016/j.immuni.2005.09.015;
RA Schmitz J., Owyang A., Oldham E., Song Y., Murphy E., McClanahan T.K.,
RA Zurawski G., Moshrefi M., Qin J., Li X., Gorman D.M., Bazan J.F.,
RA Kastelein R.A.;
RT "IL-33, an interleukin-1-like cytokine that signals via the IL-1
RT receptor-related protein ST 2 and induces T helper type 2-associated
RT cytokines.";
RL Immunity 23:479-490(2005).
RN [14]
RP IDENTIFICATION IN COMPLEX WITH IRAK1; MYD88; PELI1 AND TRAF6.
RX PubMed=16951688; DOI=10.1038/ni1383;
RA Choi K.C., Lee Y.S., Lim S., Choi H.K., Lee C.H., Lee E.K., Hong S.,
RA Kim I.H., Kim S.J., Park S.H.;
RT "Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor
RT signaling through direct interaction with the adaptor Pellino-1.";
RL Nat. Immunol. 7:1057-1065(2006).
RN [15]
RP FUNCTION IN PHOSPHORYLATION OF NCF1.
RX PubMed=17217339; DOI=10.1042/BJ20061184;
RA Pacquelet S., Johnson J.L., Ellis B.A., Brzezinska A.A., Lane W.S.,
RA Munafo D.B., Catz S.D.;
RT "Cross-talk between IRAK-4 and the NADPH oxidase.";
RL Biochem. J. 403:451-461(2007).
RN [16]
RP FUNCTION IN TLR7 SIGNALING PATHWAY.
RX PubMed=17337443; DOI=10.1074/jbc.M700548200;
RA Koziczak-Holbro M., Joyce C., Gluck A., Kinzel B., Muller M.,
RA Tschopp C., Mathison J.C., Davis C.N., Gram H.;
RT "IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor-
RT and toll-like receptor 7-mediated signaling and gene expression.";
RL J. Biol. Chem. 282:13552-13560(2007).
RN [17]
RP INVOLVEMENT IN IPD1.
RX PubMed=16950813; DOI=10.1136/jmg.2006.044446;
RA Ku C.-L., Picard C., Erdos M., Jeurissen A., Bustamante J., Puel A.,
RA von Bernuth H., Filipe-Santos O., Chang H.-H., Lawrence T., Raes M.,
RA Marodi L., Bossuyt X., Casanova J.-L.;
RT "IRAK4 and NEMO mutations in otherwise healthy children with recurrent
RT invasive pneumococcal disease.";
RL J. Med. Genet. 44:16-23(2007).
RN [18]
RP FUNCTION IN PHOSPHORYLATION OF PELI1.
RX PubMed=17997719; DOI=10.1042/BJ20071365;
RA Ordureau A., Smith H., Windheim M., Peggie M., Carrick E., Morrice N.,
RA Cohen P.;
RT "The IRAK-catalysed activation of the E3 ligase function of Pellino
RT isoforms induces the Lys63-linked polyubiquitination of IRAK1.";
RL Biochem. J. 409:43-52(2008).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [22]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-34, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [23]
RP FUNCTION IN PHOSPHORYLATION OF TIRAP.
RX PubMed=20400509; DOI=10.1074/jbc.M109.098137;
RA Dunne A., Carpenter S., Brikos C., Gray P., Strelow A., Wesche H.,
RA Morrice N., O'Neill L.A.;
RT "IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and
RT degradation of MyD88 adaptor-like (Mal).";
RL J. Biol. Chem. 285:18276-18282(2010).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [26]
RP SUBCELLULAR LOCATION.
RX PubMed=21325272; DOI=10.1074/jbc.M110.199653;
RA Nagpal K., Plantinga T.S., Sirois C.M., Monks B.G., Latz E.,
RA Netea M.G., Golenbock D.T.;
RT "Natural loss-of-function mutation of myeloid differentiation protein
RT 88 disrupts its ability to form Myddosomes.";
RL J. Biol. Chem. 286:11875-11882(2011).
RN [27]
RP REVIEW ON MYDDOSOME.
RX PubMed=21269878; DOI=10.1016/j.it.2010.12.005;
RA Gay N.J., Gangloff M., O'Neill L.A.;
RT "What the Myddosome structure tells us about the initiation of innate
RT immunity.";
RL Trends Immunol. 32:104-109(2011).
RN [28]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 154-460 IN COMPLEX WITH
RP INHIBITORS, AND PHOSPHORYLATION AT THR-345 AND SER-346.
RX PubMed=17161373; DOI=10.1016/j.str.2006.11.001;
RA Wang Z., Liu J., Sudom A., Ayres M., Li S., Wesche H., Powers J.P.,
RA Walker N.P.C.;
RT "Crystal structures of IRAK-4 kinase in complex with inhibitors: a
RT serine/threonine kinase with tyrosine as a gatekeeper.";
RL Structure 14:1835-1844(2006).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 163-460, AND PHOSPHORYLATION
RP AT THR-342 AND THR-345.
RA Mol C.D., Arduini R.M., Baker D.P., Chien E.Y., Dougan D.R.,
RA Friedman J., Gibaja V., Hession C.A., Horne A.;
RT "Crystal structures of the apo and inhibited IRAK4 kinase domain.";
RL Submitted (DEC-2006) to the PDB data bank.
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 160-460 IN COMPLEX WITH ATP
RP ANALOGS, PHOSPHORYLATION AT THR-342; THR-345 AND SER-346, AND
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=17312103;
RA Kuglstatter A., Villasenor A.G., Shaw D., Lee S.W., Tsing S., Niu L.,
RA Song K.W., Barnett J.W., Browner M.F.;
RT "Cutting Edge: IL-1 receptor-associated kinase 4 structures reveal
RT novel features and multiple conformations.";
RL J. Immunol. 178:2641-2645(2007).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (3.40 ANGSTROMS) OF 4-106.
RX PubMed=20485341; DOI=10.1038/nature09121;
RA Lin S.-C., Lo Y.-C., Wu H.;
RT "Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R
RT signalling.";
RL Nature 465:885-890(2010).
RN [33]
RP VARIANTS [LARGE SCALE ANALYSIS] VAL-5; VAL-355; HIS-391 AND THR-428.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine-protein kinase that plays a critical
CC role in initiating innate immune response against foreign
CC pathogens. Involved in Toll-like receptor (TLR) and IL-1R
CC signaling pathways. Is rapidly recruited by MYD88 to the receptor-
CC signaling complex upon TLR activation to form the Myddosome
CC together with IRAK2. Phosphorylates initially IRAK1, thus
CC stimulating the kinase activity and intensive autophosphorylation
CC of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins
CC (PELI1, PELI2 and PELI3) to promote pellino-mediated
CC polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of
CC IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the
CC IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In
CC turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB)
CC leading to NF-kappa-B nuclear translocation and activation.
CC Alternatively, phosphorylates TIRAP to promote its ubiquitination
CC and subsequent degradation. Phosphorylates NCF1 and regulates
CC NADPH oxidase activation after LPS stimulation suggesting a
CC similar mechanism during microbial infections.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=650 uM for ATP (at pH 7.5);
CC KM=1100 uM for substrate (at pH 7.5);
CC -!- SUBUNIT: Associates with MYD88 and IRAK2 to form a ternary complex
CC called the Myddosome. Once phosphorylated, IRAK4 dissociates from
CC the receptor complex and then associates with the TNF receptor-
CC associated factor 6 (TRAF6), IRAK1, and PELI1; this intermediate
CC complex is required for subsequent NF-kappa-B activation. Direct
CC binding of SMAD6 to PELI1 prevents complex formation and hence
CC negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-
CC mediated gene expression. Interacts with IL1RL1.
CC -!- INTERACTION:
CC Q9HAT8:PELI2; NbExp=3; IntAct=EBI-448378, EBI-448407;
CC P58753:TIRAP; NbExp=2; IntAct=EBI-448378, EBI-528644;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9NWZ3-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NWZ3-2; Sequence=VSP_041556;
CC -!- PTM: Phosphorylated (By similarity).
CC -!- DISEASE: Recurrent isolated invasive pneumococcal disease 1 (IPD1)
CC [MIM:610799]: Recurrent invasive pneumococcal disease (IPD) is
CC defined as two episodes of IPD occurring at least 1 month apart,
CC whether caused by the same or different serotypes or strains.
CC Recurrent IPD occurs in at least 2% of patients in most series,
CC making IPD the most important known risk factor for subsequent
CC IPD. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: IRAK4 deficiency (IRAK4D) [MIM:607676]: Causes
CC extracellular pyogenic bacterial and fungal infections in
CC otherwise healthy children. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. Pelle subfamily.
CC -!- SIMILARITY: Contains 1 death domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=IRAK4base; Note=IRAK4 mutation db;
CC URL="http://bioinf.uta.fi/IRAK4base/";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/irak4/";
CC -----------------------------------------------------------------------
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DR EMBL; AF445802; AAM15772.1; -; mRNA.
DR EMBL; AF155118; AAD42884.1; -; mRNA.
DR EMBL; AY340964; AAR02360.1; -; mRNA.
DR EMBL; AY340965; AAR02361.1; -; mRNA.
DR EMBL; AY340966; AAR02362.1; -; mRNA.
DR EMBL; AY340967; AAR02363.1; -; mRNA.
DR EMBL; AK000528; BAA91232.1; -; mRNA.
DR EMBL; AK299944; BAG61774.1; -; mRNA.
DR EMBL; AY186092; AAN75440.1; -; Genomic_DNA.
DR EMBL; AC093012; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC013316; AAH13316.1; -; mRNA.
DR RefSeq; NP_001107654.1; NM_001114182.2.
DR RefSeq; NP_001138728.1; NM_001145256.1.
DR RefSeq; NP_001138729.1; NM_001145257.1.
DR RefSeq; NP_001138730.1; NM_001145258.1.
DR RefSeq; NP_057207.2; NM_016123.3.
DR RefSeq; XP_005269000.1; XM_005268943.1.
DR RefSeq; XP_005269001.1; XM_005268944.1.
DR RefSeq; XP_005269002.1; XM_005268945.1.
DR RefSeq; XP_005269003.1; XM_005268946.1.
DR RefSeq; XP_005269004.1; XM_005268947.1.
DR RefSeq; XP_005269005.1; XM_005268948.1.
DR RefSeq; XP_005269006.1; XM_005268949.1.
DR UniGene; Hs.138499; -.
DR PDB; 2NRU; X-ray; 2.00 A; A/B/C/D=154-460.
DR PDB; 2NRY; X-ray; 2.15 A; A/B/C/D=154-460.
DR PDB; 2O8Y; X-ray; 2.40 A; A/B=163-460.
DR PDB; 2OIB; X-ray; 2.00 A; A/B/C/D=160-460.
DR PDB; 2OIC; X-ray; 2.40 A; A/B/C/D=160-460.
DR PDB; 2OID; X-ray; 2.30 A; A/B/C/D=160-460.
DR PDB; 3MOP; X-ray; 3.40 A; G/H/I/J=4-106.
DR PDBsum; 2NRU; -.
DR PDBsum; 2NRY; -.
DR PDBsum; 2O8Y; -.
DR PDBsum; 2OIB; -.
DR PDBsum; 2OIC; -.
DR PDBsum; 2OID; -.
DR PDBsum; 3MOP; -.
DR ProteinModelPortal; Q9NWZ3; -.
DR SMR; Q9NWZ3; 4-458.
DR DIP; DIP-31351N; -.
DR IntAct; Q9NWZ3; 10.
DR MINT; MINT-1383671; -.
DR STRING; 9606.ENSP00000349096; -.
DR BindingDB; Q9NWZ3; -.
DR ChEMBL; CHEMBL3778; -.
DR GuidetoPHARMACOLOGY; 2045; -.
DR DMDM; 50401181; -.
DR PaxDb; Q9NWZ3; -.
DR PRIDE; Q9NWZ3; -.
DR DNASU; 51135; -.
DR Ensembl; ENST00000431837; ENSP00000390327; ENSG00000198001.
DR Ensembl; ENST00000440781; ENSP00000408734; ENSG00000198001.
DR Ensembl; ENST00000448290; ENSP00000390651; ENSG00000198001.
DR Ensembl; ENST00000551736; ENSP00000446490; ENSG00000198001.
DR GeneID; 51135; -.
DR KEGG; hsa:51135; -.
DR UCSC; uc001rnt.3; human.
DR CTD; 51135; -.
DR GeneCards; GC12P044152; -.
DR HGNC; HGNC:17967; IRAK4.
DR HPA; CAB016685; -.
DR HPA; CAB022077; -.
DR HPA; HPA000924; -.
DR MIM; 606883; gene.
DR MIM; 607676; phenotype.
DR MIM; 610799; phenotype.
DR neXtProt; NX_Q9NWZ3; -.
DR Orphanet; 70592; Immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency.
DR PharmGKB; PA134914577; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000116550; -.
DR HOVERGEN; HBG066836; -.
DR InParanoid; Q9NWZ3; -.
DR KO; K04733; -.
DR OMA; YMPPDSS; -.
DR OrthoDB; EOG7MD4Q1; -.
DR PhylomeDB; Q9NWZ3; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q9NWZ3; -.
DR EvolutionaryTrace; Q9NWZ3; -.
DR GenomeRNAi; 51135; -.
DR NextBio; 53983; -.
DR PRO; PR:Q9NWZ3; -.
DR ArrayExpress; Q9NWZ3; -.
DR Bgee; Q9NWZ3; -.
DR CleanEx; HS_IRAK4; -.
DR Genevestigator; Q9NWZ3; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; EXP:Reactome.
DR GO; GO:0001816; P:cytokine production; IEA:Ensembl.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:UniProtKB.
DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:UniProtKB.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR011029; DEATH-like_dom.
DR InterPro; IPR017428; IL-1_rcpt-assoc_kin4.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR Pfam; PF00069; Pkinase; 1.
DR PIRSF; PIRSF038189; IRAK4; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50017; DEATH_DOMAIN; FALSE_NEG.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; FALSE_NEG.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding;
KW Complete proteome; Cytoplasm; Immunity; Innate immunity; Kinase;
KW Magnesium; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Reference proteome; Serine/threonine-protein kinase; Transferase.
FT CHAIN 1 460 Interleukin-1 receptor-associated kinase
FT 4.
FT /FTId=PRO_0000086035.
FT DOMAIN 20 104 Death.
FT DOMAIN 186 454 Protein kinase.
FT NP_BIND 192 200 ATP (By similarity).
FT NP_BIND 313 316 ATP.
FT ACT_SITE 311 311 Proton acceptor (By similarity).
FT BINDING 213 213 ATP.
FT BINDING 329 329 ATP.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 34 34 N6-acetyllysine.
FT MOD_RES 342 342 Phosphothreonine.
FT MOD_RES 345 345 Phosphothreonine.
FT MOD_RES 346 346 Phosphoserine.
FT VAR_SEQ 1 124 Missing (in isoform 2).
FT /FTId=VSP_041556.
FT VARIANT 5 5 I -> V (in dbSNP:rs56312115).
FT /FTId=VAR_040588.
FT VARIANT 98 98 S -> R (in dbSNP:rs4251469).
FT /FTId=VAR_019354.
FT VARIANT 355 355 M -> V.
FT /FTId=VAR_040589.
FT VARIANT 390 390 H -> R (in dbSNP:rs4251583).
FT /FTId=VAR_019355.
FT VARIANT 391 391 R -> H (in dbSNP:rs55944915).
FT /FTId=VAR_040590.
FT VARIANT 428 428 A -> T (in dbSNP:rs4251545).
FT /FTId=VAR_019356.
FT MUTAGEN 213 213 K->A: Loss of kinase activity.
FT CONFLICT 81 81 V -> A (in Ref. 1; AAM15772).
FT CONFLICT 432 432 V -> G (in Ref. 2; AAD42884).
FT CONFLICT 437 437 L -> R (in Ref. 2; AAD42884).
FT CONFLICT 444 444 R -> S (in Ref. 2; AAD42884).
FT CONFLICT 451 451 Q -> H (in Ref. 2; AAD42884).
FT HELIX 11 13
FT HELIX 16 26
FT HELIX 31 38
FT STRAND 42 48
FT HELIX 50 57
FT HELIX 58 60
FT TURN 61 63
FT HELIX 66 73
FT TURN 74 77
FT HELIX 81 89
FT TURN 90 92
FT HELIX 94 100
FT STRAND 102 104
FT STRAND 166 168
FT HELIX 170 176
FT TURN 177 180
FT TURN 185 188
FT STRAND 191 194
FT STRAND 196 207
FT STRAND 209 215
FT TURN 223 225
FT HELIX 226 239
FT STRAND 248 252
FT STRAND 254 257
FT STRAND 259 263
FT HELIX 270 275
FT HELIX 277 279
FT HELIX 285 304
FT HELIX 314 316
FT STRAND 317 319
FT STRAND 325 327
FT HELIX 352 354
FT HELIX 357 360
FT HELIX 367 382
FT STRAND 391 395
FT HELIX 398 404
FT HELIX 410 413
FT HELIX 423 436
FT TURN 441 443
FT HELIX 447 457
SQ SEQUENCE 460 AA; 51530 MW; 6C8156ADF25FF81E CRC64;
MNKPITPSTY VRCLNVGLIR KLSDFIDPQE GWKKLAVAIK KPSGDDRYNQ FHIRRFEALL
QTGKSPTSEL LFDWGTTNCT VGDLVDLLIQ NEFFAPASLL LPDAVPKTAN TLPSKEAITV
QQKQMPFCDK DRTLMTPVQN LEQSYMPPDS SSPENKSLEV SDTRFHSFSF YELKNVTNNF
DERPISVGGN KMGEGGFGVV YKGYVNNTTV AVKKLAAMVD ITTEELKQQF DQEIKVMAKC
QHENLVELLG FSSDGDDLCL VYVYMPNGSL LDRLSCLDGT PPLSWHMRCK IAQGAANGIN
FLHENHHIHR DIKSANILLD EAFTAKISDF GLARASEKFA QTVMTSRIVG TTAYMAPEAL
RGEITPKSDI YSFGVVLLEI ITGLPAVDEH REPQLLLDIK EEIEDEEKTI EDYIDKKMND
ADSTSVEAMY SVASQCLHEK KNKRPDIKKV QQLLQEMTAS
//
MIM
606883
*RECORD*
*FIELD* NO
606883
*FIELD* TI
*606883 INTERLEUKIN 1 RECEPTOR-ASSOCIATED KINASE 4; IRAK4
;;REN64
*FIELD* TX
DESCRIPTION
read more
Interleukin-1 receptor (see IL1R; 147810)-associated kinases (e.g.,
IRAK1; 300283) are important mediators in the signal transduction of
Toll-like receptor (TLR, e.g., TLR4; 603030) and IL1R family members,
collectively referred to as TIRs. IRAK4 functions in this signal
transduction pathway (Li et al., 2002).
CLONING
By SEREX (serologic analysis of recombinant cDNA expression libraries)
screening of renal tumors, Scanlan et al. (1999) identified multiple
antigens, including REN64. The deduced 460-amino acid protein is
strongly expressed in kidney, as determined by immunohistochemistry.
RT-PCR analysis detected expression in all 6 tissues tested (lung,
testis, small intestine, breast, liver, and placenta).
By database searching for IRAK-like sequences and PCR of a universal
cDNA library, Li et al. (2002) obtained a cDNA encoding IRAK4, which is
98% identical to REN64. The predicted protein is 84% identical to the
mouse protein and, like IRAK1, IRAK2 (603304), IRAKM (604459), and the
Drosophila Pelle protein, it has an N-terminal death domain and a
central kinase domain. Unlike the other IRAK proteins, however, but
similar to Pelle, IRAK4 has a short C-terminal domain. Northern blot
analysis revealed expression of 3.0- and 4.4-kb transcripts, with
strongest expression in kidney and liver. RT-PCR analysis detected wide,
low-level expression of IRAK4.
MAPPING
Scott (2002) mapped the REN64/IRAK4 gene to chromosome 12 based on
similarity between the REN64 sequence (GenBank GENBANK AF155118) and a
chromosome 12 clone (GenBank GENBANK AC093012). Gross (2011) mapped the
IRAK4 gene to chromosome 12q12 based on an alignment of the IRAK4
sequence (GenBank GENBANK AF155118) with the genomic sequence (GRCh37).
GENE FUNCTION
Functional analysis by Li et al. (2002) determined that IRAK4, like
IRAK1 and Pelle, has auto- and cross-phosphorylation kinase activity.
Precipitation and binding analyses showed weak interaction between IRAK4
and IRAK1, but IRAK4 did not interact with other IRAK family members.
Overexpressed IRAK4 interacted with MYD88 (602170) and TRAF6 (602355)
and activated mitogen-activated protein kinase (MAPK) and nuclear factor
kappa-B (NFKB; 164011) pathways. Endogenous IRAK4 associated in a
transient IL1 (see 147720)-dependent manner with unmodified IRAK1 and
TRAF6. Luciferase reporter analysis showed that IRAK4 lacking the kinase
domain inhibited IL1- but not tumor necrosis factor (TNF; 191160)-
induced NFKB and IRAK1 activation. SDS-PAGE and autoradiographic
analysis indicated that IRAK4 phosphorylates and activates IRAK1 at
thr387, but not vice versa. Li et al. (2002) proposed that IRAK4 acts
upstream of other IRAKs and may function as an IRAK1 kinase, triggering
a cascade of phosphorylation events.
Yang et al. (2005) found that production of IFNA (147660)/IFNB (147640)
and IFNL (IL29; 607403) in response TLR7 (300365), TLR8 (600366), and
TLR9 (605474) stimulation was abolished in IRAK4-deficient blood cells
(see 607676). However, IFNA/IFNB and IFNL production in response to 9 of
11 viruses was normal or weakly affected in IRAK4-deficient blood cells.
Stimulation with TLR3 (603029) and TLR4 agonists induced normal levels
of these interferons in IRAK4-deficient blood cells, suggesting that
IRAK4-deficient patients may use these TLRs or a TLR-independent
mechanism to control viral infections.
Suzuki et al. (2006) found that Irak4 was critical for several T-cell
functions in mice in vitro and in vivo. Luciferase reporter analysis
indicated that Irak4 was directly involved in signaling for Nfkb, but
not Nfat (see 600489), in T cells. Western blot and confocal microscopy
analyses showed that phosphorylation of Pkc-theta (PRKCQ; 600448) was
impaired in stimulated Irak4 -/- T cells, but recruitment of Pkc-theta
into the immunologic synapse was normal. Suzuki et al. (2006) concluded
that IRAK4 is involved in both the innate immune response and the
acquired T-cell response.
Ku et al. (2007) tested TLR responses of whole blood and individual
leukocyte subsets in 28 patients with IRAK4 deficiency and found that
only the TLR3 agonist poly(I:C) could induce production of 11 non-IFN
cytokines. The TLR4 agonist, LPS, could induce some responses in myeloid
dendritic cells and monocyte-derived dendritic cells. Most patients
suffered from invasive and often recurrent pneumococcal disease, but
other infections, except for severe staphylococcal disease, were rare.
Nearly half of the patients died. Death occurred only in patients 8
years old and younger, and invasive disease occurred only in those 14
years old and younger. Ku et al. (2007) concluded that IRAK4-dependent
TLRs and IL1Rs are vital for childhood immunity to pyogenic bacteria,
particularly S. pneumoniae, but they are not essential for protective
immunity to most infections.
By studying responses to the TLR4 ligand, LPS, and to the bacterial
chemoattractant, fMLP, in polymorphonuclear neutrophils (PMNs) from 1
patient with IRAK4 deficiency and 3 patients with NEMO (300248)
deficiency causing X-linked hyper-IgM immunodeficiency with ectodermal
dysplasia (300291), Singh et al. (2009) demonstrated reduced or absent
superoxide production after impaired priming and activation of the
oligomeric neutrophil NADPH oxidase (NOX; see 300481). The response was
particularly weak or absent in IRAK4-deficient PMNs. NEMO-deficient PMNs
had a phenotype intermediate between IRAK4-deficient PMNs and normal
PMNs. Decreased LPS- and fMLP-induced phosphorylation of p38 (MAPK14;
600289) was observed in both deficiencies. Singh et al. (2009) proposed
that decreased activation of NOX may contribute to increased risk of
infection in patients with IRAK4 deficiency or NEMO deficiency.
BIOCHEMICAL FEATURES
- Crystal Structure
Lin et al. (2010) reported the crystal structure of the
MyD88-IRAK4-IRAK2 death domain complex, which revealed a left-handed
helical oligomer that consists of 6 MyD88, 4 IRAK4, and 4 IRAK2 death
domains. Assembly of this helical signaling tower is hierarchical, in
which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the
IRAK4 substrates IRAK2 or the related IRAK1. Formation of these
myddosome complexes brings the kinase domains of IRAKs into proximity
for phosphorylation and activation. Composite binding sites are required
for recruitment of the individual death domains in the complex, which
are confirmed by mutagenesis and previously identified signaling
mutations. Specificities of myddosome formation are dictated by both
molecular complementarity and correspondence of surface electrostatics.
MOLECULAR GENETICS
- IRAK4 Deficiency
Deficiency of IRAK4 (607676) causes extracellular pyogenic bacterial and
fungal infections in childhood (Picard et al., 2003, Day et al., 2004).
In 3 unrelated patients with pyogenic bacterial infections, Picard et
al. (2003) identified homozygosity for mutations in the IRAK4 gene
(e.g., 606883.0001).
Medvedev et al. (2003) reported a patient with recurrent bacterial
infections who was nonresponsive to gram-negative lipopolysaccharide
(LPS) in vivo and hyporesponsive to IL1 and LPS in vitro. The patient
was compound heterozygous for 2 mutations in the IRAK4 gene (606883.0002
and 606883.0003).
Hoarau et al. (2007) investigated a 14-year-old French boy with IRAK4
deficiency who was compound heterozygous for an arg12-to-cys (R12C;
606883.0006) mutation in the death domain of IRAK4 and a splice-site
mutation in intron 7 (606883.0007) that resulted in skipping of exon 7
and a premature termination codon at position 249. Western blot analysis
of the patient's polymorphonuclear neutrophils (PMNs) showed a
nontruncated IRAK4 protein. Stimulation with TLR agonists revealed the
absence of IRAK1 phosphorylation and impaired PMN responses. However,
responses to the TLR9 agonist CpG were normal, except for cytokine
production. Impairment of TLR9 responses was observed after pretreatment
with PI3K (see 601232) inhibitors. Hoarau et al. (2007) proposed that
there may be an alternative TLR9 pathway leading to PI3K activation
independently of the classical MYD88-IRAK4 pathway.
- Invasive Pneumococcal Disease
Ku et al. (2007) reported 2 otherwise healthy, unrelated children with
recurrent invasive pneumococcal disease (IPD) as the only clinical
infectious manifestation of an inherited disorder in nuclear
factor-kappa-B (NFKB; see 164011)-dependent immunity. One child (IPD1;
610799) was a compound heterozygote for 2 germline mutations in IRAK4
(606883.0004, 606883.0005), and had impaired cellular responses to
interleukin-1 receptor (IL1R; 147810) and Toll-like receptor (see TLR1,
601194) stimulation. The other child (IPD2; 300640) carried a hemizygous
mutation in NEMO (300248.0023), associated with a broader impairment of
nuclear factor-kappa-B activation, with impaired cellular response to
IL1R, TLR, and tumor necrosis factor receptor (see 191190) stimulation.
ANIMAL MODEL
By gene targeting, Suzuki et al. (2002) generated mice deficient in
Irak4. Mutant mice and macrophages or embryonic fibroblasts (MEFs) from
these mice were unable to respond to Il1 by production of Il6 (147620),
Tnf, or nitric oxide, or by activation of Nfkb or Jnk (601158).
Responses to Tnf, however, were intact, suggesting that the defect was
specific for Il1. Analysis of responses to LPS, bacterial DNA
(unmethylated CpG), peptidoglycan, or viral RNA extended the importance
of Irak4 to Tlr4, Tlr9, Tlr2 (603028), and Tlr3, respectively, which use
signaling mechanisms similar to IL1R. Challenge of Irak4 -/- mice with
lymphocytic choriomeningitis virus showed reduced production of
gamma-interferon (IFNG; 147570) by natural killer cells, but no loss of
cytolytic function of these cells. Challenge with Staphylococcus aureus
was lethal in all mutant mice but not in most wildtype mice. Luciferase
reporter analysis suggested that Irak4 acts upstream of Myd88 and Mal
(606252) and downstream of Traf6.
*FIELD* AV
.0001
IRAK4 DEFICIENCY
IRAK4, 1-BP DEL, 821T
In a Saudi Arabian child who had recurrent pyogenic bacterial infections
(607676), Picard et al. (2003) identified a homozygous deletion of
thymidine at nucleotide 821 in exon 7 of the IRAK4 gene (821delT), which
resulted in a premature termination codon at position 287. No IRAK4 mRNA
or protein could be detected. The healthy, consanguineous parents were
heterozygous for this deletion. The mutation was not identified in 60
healthy controls.
.0002
IRAK4 DEFICIENCY
IRAK4, GLN293TER
In 2 unrelated individuals with extracellular pyogenic bacterial
infections in childhood (607676), Picard et al. (2003) identified
homozygosity for an 877C-T transition in exon 8 of the IRAK4 gene,
leading to a gln293-to-ter (Q293X) substitution. No IRAK4 mRNA was
identified in these patients, nor was protein identified by Western
blot. The parents of 1 patient were unavailable for study. In the second
patient, the mother was heterozygous for the mutation and the child
inherited 2 maternal copies owing to segmental uniparental isodisomy.
The mutation was not found in 60 healthy individuals.
Medvedev et al. (2003) reported a patient with recurrent bacterial
infections who was compound heterozygous for 2 mutations in the IRAK4
gene, Q293X and a 2-bp deletion (AC) at nucleotide 620 (606883.0003).
Both mutations resulted in proteins with intact death domains but
truncated kinase domains, precluding expression of full-length IRAK4 and
conferring a recessive phenotype.
Davidson et al. (2006) identified homozygosity for the Q293X mutation in
a patient with recurrent Streptococcus pneumonia bacteremia and in the
patient's deceased older brother. The patient's parents and 2 healthy
brothers were hemizygous for the mutation, and the mutation was not
present in controls. Characterization of the patient's IRAK4-deficient
primary dermal fibroblasts and peripheral blood mononuclear cells
revealed cell type-specific and ligand-specific defects in cytokine
responses.
.0003
IRAK4 DEFICIENCY
IRAK4, 2-BP DEL, 620AC
Medvedev et al. (2003) reported a patient with recurrent bacterial
infections (607676) who was compound heterozygous for 2 mutations in the
IRAK4 gene, gln293 to ter (Q293X; 606883.0002) and a 2-bp deletion (AC)
at nucleotide 620. Both mutations resulted in proteins with intact death
domains but truncated kinase domains, precluding expression of
full-length IRAK4 and conferring a recessive phenotype.
.0004
INVASIVE PNEUMOCOCCAL DISEASE, RECURRENT ISOLATED, 1
IRAK4, IVS10, G-T, -1
In a 7-year-old boy born of unrelated Hungarian parents, Ku et al.
(2007) found that recurrent invasive pneumococcal disease (IPD1; 610799)
was related to compound heterozygosity for 2 mutations in the IRAK4
gene, located in the intron between exons 10 and 11: 1189-1G-T and
1188+520A-G (606883.0005). The 1189-1G-T mutation was carried by the
father, and 1188+520A-G by the mother.
.0005
INVASIVE PNEUMOCOCCAL DISEASE, RECURRENT ISOLATED, 1
IRAK4, IVS10 +520A-G
See 606883.0004 and Ku et al. (2007).
.0006
IRAK4 DEFICIENCY
IRAK4, ARG12CYS
Hoarau et al. (2007) investigated a 14-year-old French boy of healthy,
unrelated patients with IRAK4 deficiency (607676) characterized by
recurrent infections, osteomyelitis, and cellulitis beginning at age 15
days. Apart from elevated C-reactive protein (CRP; 123260) and very low
PMN numbers, his immunologic status was normal. Hoarau et al. (2007)
found that the patient was compound heterozygous for 2 mutations in the
IRAK4 gene. He had a C-to-T transition at cDNA position 34, resulting in
an arg12-to-cys (R12C) mutation in the death domain of IRAK4. The R12C
mutation was inherited from the father in association with a predicted
benign arg391-to-his (R391H) substitution. The second pathogenic
mutation, which was inherited from the mother, was a G-to-T transversion
at position +5 of intron 7 (cDNA position 831+5G-T) that resulted in
skipping of exon 7 and a premature termination codon at position 249.
Western blot analysis of the patient's PMNs showed a nontruncated IRAK4
protein. Stimulation with TLR agonists revealed the absence of IRAK1
(300283) phosphorylation and impaired PMN responses. However, responses
to the TLR9 (605474) agonist CpG were normal, except for cytokine
production. Impairment of TLR9 responses was observed after pretreatment
with PI3K (see 601232) inhibitors. Hoarau et al. (2007) proposed that
there may be an alternative TLR9 pathway leading to PI3K activation
independently of the classical MYD88 (602170)-IRAK4 pathway.
.0007
IRAK4 DEFICIENCY
IRAK4, IVS7DS, G-T, +5
See 606883.0006 and Hoarau et al. (2007).
*FIELD* RF
1. Davidson, D. J.; Currie, A. J.; Bowdish, D. M. E.; Brown, K. L.;
Rosenberger, C. M.; Ma, R. C.; Bylund, J.; Campsall, P. A.; Puel,
A.; Picard, C.; Casanova, J.-L.; Turvey, S. E.; Hancock, R. E. W.;
Devon, R. S.; Speert, D. P.: IRAK-4 mutation (Q293X): rapid detection
and characterization of defective post-transcriptional TLR/IL-1R responses
in human myeloid and non-myeloid cells. J. Immun. 177: 8202-8211,
2006.
2. Day, N.; Tangsinmankong, N.; Ochs, H.; Rucker, R.; Picard, C.;
Casanova, J.-L.; Haraguchi, S.; Good, R.: Interleukin receptor-associated
kinase (IRAK-4) deficiency associated with bacterial infections and
failure to sustain antibody responses. J. Pediat. 144: 524-526,
2004.
3. Gross, M. B.: Personal Communication. Baltimore, Md. 2/4/2011.
4. Hoarau, C.; Gerard, B.; Lescanne, E.; Henry, D.; Francois, S.;
Lacapere, J.-J.; El Benna, J.; Dang, P. M.-C.; Grandchamp, B.; Lebranchu,
Y.; Gougerot-Pocidalo, M.-A.; Elbim, C.: TLR9 activation induces
normal neutrophil responses in a child with IRAK-4 deficiency: involvement
of the direct PI3K pathway. J. Immun. 179: 4754-4765, 2007.
5. Ku, C.-L.; Picard, C.; Erdos, M.; Jeurissen, A.; Bustamante, J.;
Puel, A.; von Bernuth, H.; Filipe-Santos, O.; Chang, H.-H.; Lawrence,
T.; Raes, M.; Marodi, L.; Bossuyt, X.; Casanova, J.-L.: IRAK4 and
NEMO mutations in otherwise healthy children with recurrent invasive
pneumococcal disease. J. Med. Genet. 44: 16-23, 2007.
6. Ku, C.-L.; von Bernuth, H.; Picard, C.; Zhang, S.-Y.; Chang, H.-H.;
Yang, K.; Chrabieh, M.; Issekutz, A. C.; Cunningham, C. K.; Gallin,
J.; Holland, S. M.; Roifman, C.; and 25 others: Selective predisposition
to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent
TLRs are otherwise redundant in protective immunity. J. Exp. Med. 204:
2407-2422, 2007.
7. Li, S.; Strelow, A.; Fontana, E. J.; Wesche, H.: IRAK-4: a novel
member of the IRAK family with the properties of an IRAK-kinase. Proc.
Nat. Acad. Sci. 99: 5567-5572, 2002.
8. Lin, S.-C.; Lo, Y.-C.; Wu, H.: Helical assembly in the MyD88-IRAK4-IRAK2
complex in TLR/IL-1R signalling. Nature 465: 885-890, 2010.
9. Medvedev, A. E.; Lentschat, A.; Kuhns, D. B.; Blanco, J. C. G.;
Salkowski, C.; Zhang, S.; Arditi, M.; Gallin, J. I.; Vogel, S. N.
: Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide
and interleukin-1 in a patient with recurrent bacterial infections. J.
Exp. Med. 198: 521-531, 2003.
10. Picard, C.; Puel, A.; Bonnet, M.; Ku, C.-L.; Bustamante, J.; Yang,
K.; Soudais, C.; Dupuis, S.; Feinberg, J.; Fieschi, C.; Elbim, C.;
Hitchcock, R.; and 18 others: Pyogenic bacterial infections in
humans with IRAK-4 deficiency. Science 299: 2076-2079, 2003.
11. Scanlan, M. J.; Gordon, J. D.; Williamson, B.; Stockert, E.; Bander,
N. H.; Jongeneel, V.; Gure, A. O.; Jager, D.; Jager, E.; Knuth, A.;
Chen, Y.-T.; Old, L. J.: Antigens recognized by autologous antibody
in patients with renal-cell carcinoma. Int. J. Cancer 83: 456-464,
1999.
12. Scott, A. F.: Personal Communication. Baltimore, Md. 4/25/2002.
13. Singh, A.; Zarember, K. A.; Kuhns, D. B.; Gallin, J. I.: Impaired
priming and activation of the neutrophil NADPH oxidase in patients
with IRAK4 or NEMO deficiency. J. Immun. 182: 6410-6417, 2009.
14. Suzuki, N.; Suzuki, S.; Duncan, G. S.; Millar, D. G.; Wada, T.;
Mirtsos, C.; Takada, H.; Wakeham, A.; Itie, A.; Li, S.; Penninger,
J. M.; Wesche, H.; Ohashi, P. S.; Mak, T. W.; Yeh, W.-C.: Severe
impairment of interleukin-1 and Toll-like receptor signalling in mice
lacking IRAK-4. Nature 416: 750-754, 2002.
15. Suzuki, N.; Suzuki, S.; Millar, D. G.; Unno, M.; Hara, H.; Calzascia,
T.; Yamasaki, S.; Yokosuka, T.; Chen, N.-J.; Elford, A. R.; Suzuki,
J.; Takeuchi, A.; Mirtsos, C.; Bouchard, D.; Ohashi, P. S.; Yeh, W.-C.;
Saito, T.: A critical role for the innate immune signaling molecule
IRAK-4 in T cell activation. Science 311: 1927-1932, 2006.
16. Yang, K.; Puel, A.; Zhang, S.; Eidenschenk, C.; Ku, C.-L.; Casrouge,
A.; Picard, C.; von Bernuth, H.; Senechal, B.; Plancoulaine, S.; Al-Hajjar,
S.; Al-Ghonaium, A.; and 16 others: Human TLR-7, -8-, and -9-mediated
induction of IFN-alpha/beta and -lambda is IRAK-4 dependent and redundant
for protective immunity to viruses. Immunity 23: 465-478, 2005.
*FIELD* CN
Paul J. Converse - updated: 2/28/2011
Matthew B. Gross - updated: 2/4/2011
Paul J. Converse - updated: 12/20/2010
Ada Hamosh - updated: 7/1/2010
Paul J. Converse - updated: 1/29/2009
Paul J. Converse - updated: 9/18/2007
Victor A. McKusick - updated: 2/21/2007
Paul J. Converse - updated: 4/19/2006
Paul J. Converse - updated: 3/14/2006
Paul J. Converse - updated: 2/14/2006
Natalie E. Krasikov - updated: 8/10/2004
Ada Hamosh - updated: 4/3/2003
*FIELD* CD
Paul J. Converse: 4/25/2002
*FIELD* ED
mgross: 03/01/2011
terry: 2/28/2011
mgross: 2/4/2011
terry: 12/20/2010
alopez: 7/2/2010
terry: 7/1/2010
mgross: 1/29/2009
terry: 1/29/2009
mgross: 10/25/2007
terry: 9/18/2007
alopez: 2/26/2007
terry: 2/21/2007
mgross: 4/19/2006
mgross: 3/14/2006
mgross: 2/16/2006
terry: 2/14/2006
carol: 2/14/2006
terry: 8/10/2004
joanna: 4/10/2003
alopez: 4/7/2003
terry: 4/3/2003
mgross: 4/25/2002
*RECORD*
*FIELD* NO
606883
*FIELD* TI
*606883 INTERLEUKIN 1 RECEPTOR-ASSOCIATED KINASE 4; IRAK4
;;REN64
*FIELD* TX
DESCRIPTION
read more
Interleukin-1 receptor (see IL1R; 147810)-associated kinases (e.g.,
IRAK1; 300283) are important mediators in the signal transduction of
Toll-like receptor (TLR, e.g., TLR4; 603030) and IL1R family members,
collectively referred to as TIRs. IRAK4 functions in this signal
transduction pathway (Li et al., 2002).
CLONING
By SEREX (serologic analysis of recombinant cDNA expression libraries)
screening of renal tumors, Scanlan et al. (1999) identified multiple
antigens, including REN64. The deduced 460-amino acid protein is
strongly expressed in kidney, as determined by immunohistochemistry.
RT-PCR analysis detected expression in all 6 tissues tested (lung,
testis, small intestine, breast, liver, and placenta).
By database searching for IRAK-like sequences and PCR of a universal
cDNA library, Li et al. (2002) obtained a cDNA encoding IRAK4, which is
98% identical to REN64. The predicted protein is 84% identical to the
mouse protein and, like IRAK1, IRAK2 (603304), IRAKM (604459), and the
Drosophila Pelle protein, it has an N-terminal death domain and a
central kinase domain. Unlike the other IRAK proteins, however, but
similar to Pelle, IRAK4 has a short C-terminal domain. Northern blot
analysis revealed expression of 3.0- and 4.4-kb transcripts, with
strongest expression in kidney and liver. RT-PCR analysis detected wide,
low-level expression of IRAK4.
MAPPING
Scott (2002) mapped the REN64/IRAK4 gene to chromosome 12 based on
similarity between the REN64 sequence (GenBank GENBANK AF155118) and a
chromosome 12 clone (GenBank GENBANK AC093012). Gross (2011) mapped the
IRAK4 gene to chromosome 12q12 based on an alignment of the IRAK4
sequence (GenBank GENBANK AF155118) with the genomic sequence (GRCh37).
GENE FUNCTION
Functional analysis by Li et al. (2002) determined that IRAK4, like
IRAK1 and Pelle, has auto- and cross-phosphorylation kinase activity.
Precipitation and binding analyses showed weak interaction between IRAK4
and IRAK1, but IRAK4 did not interact with other IRAK family members.
Overexpressed IRAK4 interacted with MYD88 (602170) and TRAF6 (602355)
and activated mitogen-activated protein kinase (MAPK) and nuclear factor
kappa-B (NFKB; 164011) pathways. Endogenous IRAK4 associated in a
transient IL1 (see 147720)-dependent manner with unmodified IRAK1 and
TRAF6. Luciferase reporter analysis showed that IRAK4 lacking the kinase
domain inhibited IL1- but not tumor necrosis factor (TNF; 191160)-
induced NFKB and IRAK1 activation. SDS-PAGE and autoradiographic
analysis indicated that IRAK4 phosphorylates and activates IRAK1 at
thr387, but not vice versa. Li et al. (2002) proposed that IRAK4 acts
upstream of other IRAKs and may function as an IRAK1 kinase, triggering
a cascade of phosphorylation events.
Yang et al. (2005) found that production of IFNA (147660)/IFNB (147640)
and IFNL (IL29; 607403) in response TLR7 (300365), TLR8 (600366), and
TLR9 (605474) stimulation was abolished in IRAK4-deficient blood cells
(see 607676). However, IFNA/IFNB and IFNL production in response to 9 of
11 viruses was normal or weakly affected in IRAK4-deficient blood cells.
Stimulation with TLR3 (603029) and TLR4 agonists induced normal levels
of these interferons in IRAK4-deficient blood cells, suggesting that
IRAK4-deficient patients may use these TLRs or a TLR-independent
mechanism to control viral infections.
Suzuki et al. (2006) found that Irak4 was critical for several T-cell
functions in mice in vitro and in vivo. Luciferase reporter analysis
indicated that Irak4 was directly involved in signaling for Nfkb, but
not Nfat (see 600489), in T cells. Western blot and confocal microscopy
analyses showed that phosphorylation of Pkc-theta (PRKCQ; 600448) was
impaired in stimulated Irak4 -/- T cells, but recruitment of Pkc-theta
into the immunologic synapse was normal. Suzuki et al. (2006) concluded
that IRAK4 is involved in both the innate immune response and the
acquired T-cell response.
Ku et al. (2007) tested TLR responses of whole blood and individual
leukocyte subsets in 28 patients with IRAK4 deficiency and found that
only the TLR3 agonist poly(I:C) could induce production of 11 non-IFN
cytokines. The TLR4 agonist, LPS, could induce some responses in myeloid
dendritic cells and monocyte-derived dendritic cells. Most patients
suffered from invasive and often recurrent pneumococcal disease, but
other infections, except for severe staphylococcal disease, were rare.
Nearly half of the patients died. Death occurred only in patients 8
years old and younger, and invasive disease occurred only in those 14
years old and younger. Ku et al. (2007) concluded that IRAK4-dependent
TLRs and IL1Rs are vital for childhood immunity to pyogenic bacteria,
particularly S. pneumoniae, but they are not essential for protective
immunity to most infections.
By studying responses to the TLR4 ligand, LPS, and to the bacterial
chemoattractant, fMLP, in polymorphonuclear neutrophils (PMNs) from 1
patient with IRAK4 deficiency and 3 patients with NEMO (300248)
deficiency causing X-linked hyper-IgM immunodeficiency with ectodermal
dysplasia (300291), Singh et al. (2009) demonstrated reduced or absent
superoxide production after impaired priming and activation of the
oligomeric neutrophil NADPH oxidase (NOX; see 300481). The response was
particularly weak or absent in IRAK4-deficient PMNs. NEMO-deficient PMNs
had a phenotype intermediate between IRAK4-deficient PMNs and normal
PMNs. Decreased LPS- and fMLP-induced phosphorylation of p38 (MAPK14;
600289) was observed in both deficiencies. Singh et al. (2009) proposed
that decreased activation of NOX may contribute to increased risk of
infection in patients with IRAK4 deficiency or NEMO deficiency.
BIOCHEMICAL FEATURES
- Crystal Structure
Lin et al. (2010) reported the crystal structure of the
MyD88-IRAK4-IRAK2 death domain complex, which revealed a left-handed
helical oligomer that consists of 6 MyD88, 4 IRAK4, and 4 IRAK2 death
domains. Assembly of this helical signaling tower is hierarchical, in
which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the
IRAK4 substrates IRAK2 or the related IRAK1. Formation of these
myddosome complexes brings the kinase domains of IRAKs into proximity
for phosphorylation and activation. Composite binding sites are required
for recruitment of the individual death domains in the complex, which
are confirmed by mutagenesis and previously identified signaling
mutations. Specificities of myddosome formation are dictated by both
molecular complementarity and correspondence of surface electrostatics.
MOLECULAR GENETICS
- IRAK4 Deficiency
Deficiency of IRAK4 (607676) causes extracellular pyogenic bacterial and
fungal infections in childhood (Picard et al., 2003, Day et al., 2004).
In 3 unrelated patients with pyogenic bacterial infections, Picard et
al. (2003) identified homozygosity for mutations in the IRAK4 gene
(e.g., 606883.0001).
Medvedev et al. (2003) reported a patient with recurrent bacterial
infections who was nonresponsive to gram-negative lipopolysaccharide
(LPS) in vivo and hyporesponsive to IL1 and LPS in vitro. The patient
was compound heterozygous for 2 mutations in the IRAK4 gene (606883.0002
and 606883.0003).
Hoarau et al. (2007) investigated a 14-year-old French boy with IRAK4
deficiency who was compound heterozygous for an arg12-to-cys (R12C;
606883.0006) mutation in the death domain of IRAK4 and a splice-site
mutation in intron 7 (606883.0007) that resulted in skipping of exon 7
and a premature termination codon at position 249. Western blot analysis
of the patient's polymorphonuclear neutrophils (PMNs) showed a
nontruncated IRAK4 protein. Stimulation with TLR agonists revealed the
absence of IRAK1 phosphorylation and impaired PMN responses. However,
responses to the TLR9 agonist CpG were normal, except for cytokine
production. Impairment of TLR9 responses was observed after pretreatment
with PI3K (see 601232) inhibitors. Hoarau et al. (2007) proposed that
there may be an alternative TLR9 pathway leading to PI3K activation
independently of the classical MYD88-IRAK4 pathway.
- Invasive Pneumococcal Disease
Ku et al. (2007) reported 2 otherwise healthy, unrelated children with
recurrent invasive pneumococcal disease (IPD) as the only clinical
infectious manifestation of an inherited disorder in nuclear
factor-kappa-B (NFKB; see 164011)-dependent immunity. One child (IPD1;
610799) was a compound heterozygote for 2 germline mutations in IRAK4
(606883.0004, 606883.0005), and had impaired cellular responses to
interleukin-1 receptor (IL1R; 147810) and Toll-like receptor (see TLR1,
601194) stimulation. The other child (IPD2; 300640) carried a hemizygous
mutation in NEMO (300248.0023), associated with a broader impairment of
nuclear factor-kappa-B activation, with impaired cellular response to
IL1R, TLR, and tumor necrosis factor receptor (see 191190) stimulation.
ANIMAL MODEL
By gene targeting, Suzuki et al. (2002) generated mice deficient in
Irak4. Mutant mice and macrophages or embryonic fibroblasts (MEFs) from
these mice were unable to respond to Il1 by production of Il6 (147620),
Tnf, or nitric oxide, or by activation of Nfkb or Jnk (601158).
Responses to Tnf, however, were intact, suggesting that the defect was
specific for Il1. Analysis of responses to LPS, bacterial DNA
(unmethylated CpG), peptidoglycan, or viral RNA extended the importance
of Irak4 to Tlr4, Tlr9, Tlr2 (603028), and Tlr3, respectively, which use
signaling mechanisms similar to IL1R. Challenge of Irak4 -/- mice with
lymphocytic choriomeningitis virus showed reduced production of
gamma-interferon (IFNG; 147570) by natural killer cells, but no loss of
cytolytic function of these cells. Challenge with Staphylococcus aureus
was lethal in all mutant mice but not in most wildtype mice. Luciferase
reporter analysis suggested that Irak4 acts upstream of Myd88 and Mal
(606252) and downstream of Traf6.
*FIELD* AV
.0001
IRAK4 DEFICIENCY
IRAK4, 1-BP DEL, 821T
In a Saudi Arabian child who had recurrent pyogenic bacterial infections
(607676), Picard et al. (2003) identified a homozygous deletion of
thymidine at nucleotide 821 in exon 7 of the IRAK4 gene (821delT), which
resulted in a premature termination codon at position 287. No IRAK4 mRNA
or protein could be detected. The healthy, consanguineous parents were
heterozygous for this deletion. The mutation was not identified in 60
healthy controls.
.0002
IRAK4 DEFICIENCY
IRAK4, GLN293TER
In 2 unrelated individuals with extracellular pyogenic bacterial
infections in childhood (607676), Picard et al. (2003) identified
homozygosity for an 877C-T transition in exon 8 of the IRAK4 gene,
leading to a gln293-to-ter (Q293X) substitution. No IRAK4 mRNA was
identified in these patients, nor was protein identified by Western
blot. The parents of 1 patient were unavailable for study. In the second
patient, the mother was heterozygous for the mutation and the child
inherited 2 maternal copies owing to segmental uniparental isodisomy.
The mutation was not found in 60 healthy individuals.
Medvedev et al. (2003) reported a patient with recurrent bacterial
infections who was compound heterozygous for 2 mutations in the IRAK4
gene, Q293X and a 2-bp deletion (AC) at nucleotide 620 (606883.0003).
Both mutations resulted in proteins with intact death domains but
truncated kinase domains, precluding expression of full-length IRAK4 and
conferring a recessive phenotype.
Davidson et al. (2006) identified homozygosity for the Q293X mutation in
a patient with recurrent Streptococcus pneumonia bacteremia and in the
patient's deceased older brother. The patient's parents and 2 healthy
brothers were hemizygous for the mutation, and the mutation was not
present in controls. Characterization of the patient's IRAK4-deficient
primary dermal fibroblasts and peripheral blood mononuclear cells
revealed cell type-specific and ligand-specific defects in cytokine
responses.
.0003
IRAK4 DEFICIENCY
IRAK4, 2-BP DEL, 620AC
Medvedev et al. (2003) reported a patient with recurrent bacterial
infections (607676) who was compound heterozygous for 2 mutations in the
IRAK4 gene, gln293 to ter (Q293X; 606883.0002) and a 2-bp deletion (AC)
at nucleotide 620. Both mutations resulted in proteins with intact death
domains but truncated kinase domains, precluding expression of
full-length IRAK4 and conferring a recessive phenotype.
.0004
INVASIVE PNEUMOCOCCAL DISEASE, RECURRENT ISOLATED, 1
IRAK4, IVS10, G-T, -1
In a 7-year-old boy born of unrelated Hungarian parents, Ku et al.
(2007) found that recurrent invasive pneumococcal disease (IPD1; 610799)
was related to compound heterozygosity for 2 mutations in the IRAK4
gene, located in the intron between exons 10 and 11: 1189-1G-T and
1188+520A-G (606883.0005). The 1189-1G-T mutation was carried by the
father, and 1188+520A-G by the mother.
.0005
INVASIVE PNEUMOCOCCAL DISEASE, RECURRENT ISOLATED, 1
IRAK4, IVS10 +520A-G
See 606883.0004 and Ku et al. (2007).
.0006
IRAK4 DEFICIENCY
IRAK4, ARG12CYS
Hoarau et al. (2007) investigated a 14-year-old French boy of healthy,
unrelated patients with IRAK4 deficiency (607676) characterized by
recurrent infections, osteomyelitis, and cellulitis beginning at age 15
days. Apart from elevated C-reactive protein (CRP; 123260) and very low
PMN numbers, his immunologic status was normal. Hoarau et al. (2007)
found that the patient was compound heterozygous for 2 mutations in the
IRAK4 gene. He had a C-to-T transition at cDNA position 34, resulting in
an arg12-to-cys (R12C) mutation in the death domain of IRAK4. The R12C
mutation was inherited from the father in association with a predicted
benign arg391-to-his (R391H) substitution. The second pathogenic
mutation, which was inherited from the mother, was a G-to-T transversion
at position +5 of intron 7 (cDNA position 831+5G-T) that resulted in
skipping of exon 7 and a premature termination codon at position 249.
Western blot analysis of the patient's PMNs showed a nontruncated IRAK4
protein. Stimulation with TLR agonists revealed the absence of IRAK1
(300283) phosphorylation and impaired PMN responses. However, responses
to the TLR9 (605474) agonist CpG were normal, except for cytokine
production. Impairment of TLR9 responses was observed after pretreatment
with PI3K (see 601232) inhibitors. Hoarau et al. (2007) proposed that
there may be an alternative TLR9 pathway leading to PI3K activation
independently of the classical MYD88 (602170)-IRAK4 pathway.
.0007
IRAK4 DEFICIENCY
IRAK4, IVS7DS, G-T, +5
See 606883.0006 and Hoarau et al. (2007).
*FIELD* RF
1. Davidson, D. J.; Currie, A. J.; Bowdish, D. M. E.; Brown, K. L.;
Rosenberger, C. M.; Ma, R. C.; Bylund, J.; Campsall, P. A.; Puel,
A.; Picard, C.; Casanova, J.-L.; Turvey, S. E.; Hancock, R. E. W.;
Devon, R. S.; Speert, D. P.: IRAK-4 mutation (Q293X): rapid detection
and characterization of defective post-transcriptional TLR/IL-1R responses
in human myeloid and non-myeloid cells. J. Immun. 177: 8202-8211,
2006.
2. Day, N.; Tangsinmankong, N.; Ochs, H.; Rucker, R.; Picard, C.;
Casanova, J.-L.; Haraguchi, S.; Good, R.: Interleukin receptor-associated
kinase (IRAK-4) deficiency associated with bacterial infections and
failure to sustain antibody responses. J. Pediat. 144: 524-526,
2004.
3. Gross, M. B.: Personal Communication. Baltimore, Md. 2/4/2011.
4. Hoarau, C.; Gerard, B.; Lescanne, E.; Henry, D.; Francois, S.;
Lacapere, J.-J.; El Benna, J.; Dang, P. M.-C.; Grandchamp, B.; Lebranchu,
Y.; Gougerot-Pocidalo, M.-A.; Elbim, C.: TLR9 activation induces
normal neutrophil responses in a child with IRAK-4 deficiency: involvement
of the direct PI3K pathway. J. Immun. 179: 4754-4765, 2007.
5. Ku, C.-L.; Picard, C.; Erdos, M.; Jeurissen, A.; Bustamante, J.;
Puel, A.; von Bernuth, H.; Filipe-Santos, O.; Chang, H.-H.; Lawrence,
T.; Raes, M.; Marodi, L.; Bossuyt, X.; Casanova, J.-L.: IRAK4 and
NEMO mutations in otherwise healthy children with recurrent invasive
pneumococcal disease. J. Med. Genet. 44: 16-23, 2007.
6. Ku, C.-L.; von Bernuth, H.; Picard, C.; Zhang, S.-Y.; Chang, H.-H.;
Yang, K.; Chrabieh, M.; Issekutz, A. C.; Cunningham, C. K.; Gallin,
J.; Holland, S. M.; Roifman, C.; and 25 others: Selective predisposition
to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent
TLRs are otherwise redundant in protective immunity. J. Exp. Med. 204:
2407-2422, 2007.
7. Li, S.; Strelow, A.; Fontana, E. J.; Wesche, H.: IRAK-4: a novel
member of the IRAK family with the properties of an IRAK-kinase. Proc.
Nat. Acad. Sci. 99: 5567-5572, 2002.
8. Lin, S.-C.; Lo, Y.-C.; Wu, H.: Helical assembly in the MyD88-IRAK4-IRAK2
complex in TLR/IL-1R signalling. Nature 465: 885-890, 2010.
9. Medvedev, A. E.; Lentschat, A.; Kuhns, D. B.; Blanco, J. C. G.;
Salkowski, C.; Zhang, S.; Arditi, M.; Gallin, J. I.; Vogel, S. N.
: Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide
and interleukin-1 in a patient with recurrent bacterial infections. J.
Exp. Med. 198: 521-531, 2003.
10. Picard, C.; Puel, A.; Bonnet, M.; Ku, C.-L.; Bustamante, J.; Yang,
K.; Soudais, C.; Dupuis, S.; Feinberg, J.; Fieschi, C.; Elbim, C.;
Hitchcock, R.; and 18 others: Pyogenic bacterial infections in
humans with IRAK-4 deficiency. Science 299: 2076-2079, 2003.
11. Scanlan, M. J.; Gordon, J. D.; Williamson, B.; Stockert, E.; Bander,
N. H.; Jongeneel, V.; Gure, A. O.; Jager, D.; Jager, E.; Knuth, A.;
Chen, Y.-T.; Old, L. J.: Antigens recognized by autologous antibody
in patients with renal-cell carcinoma. Int. J. Cancer 83: 456-464,
1999.
12. Scott, A. F.: Personal Communication. Baltimore, Md. 4/25/2002.
13. Singh, A.; Zarember, K. A.; Kuhns, D. B.; Gallin, J. I.: Impaired
priming and activation of the neutrophil NADPH oxidase in patients
with IRAK4 or NEMO deficiency. J. Immun. 182: 6410-6417, 2009.
14. Suzuki, N.; Suzuki, S.; Duncan, G. S.; Millar, D. G.; Wada, T.;
Mirtsos, C.; Takada, H.; Wakeham, A.; Itie, A.; Li, S.; Penninger,
J. M.; Wesche, H.; Ohashi, P. S.; Mak, T. W.; Yeh, W.-C.: Severe
impairment of interleukin-1 and Toll-like receptor signalling in mice
lacking IRAK-4. Nature 416: 750-754, 2002.
15. Suzuki, N.; Suzuki, S.; Millar, D. G.; Unno, M.; Hara, H.; Calzascia,
T.; Yamasaki, S.; Yokosuka, T.; Chen, N.-J.; Elford, A. R.; Suzuki,
J.; Takeuchi, A.; Mirtsos, C.; Bouchard, D.; Ohashi, P. S.; Yeh, W.-C.;
Saito, T.: A critical role for the innate immune signaling molecule
IRAK-4 in T cell activation. Science 311: 1927-1932, 2006.
16. Yang, K.; Puel, A.; Zhang, S.; Eidenschenk, C.; Ku, C.-L.; Casrouge,
A.; Picard, C.; von Bernuth, H.; Senechal, B.; Plancoulaine, S.; Al-Hajjar,
S.; Al-Ghonaium, A.; and 16 others: Human TLR-7, -8-, and -9-mediated
induction of IFN-alpha/beta and -lambda is IRAK-4 dependent and redundant
for protective immunity to viruses. Immunity 23: 465-478, 2005.
*FIELD* CN
Paul J. Converse - updated: 2/28/2011
Matthew B. Gross - updated: 2/4/2011
Paul J. Converse - updated: 12/20/2010
Ada Hamosh - updated: 7/1/2010
Paul J. Converse - updated: 1/29/2009
Paul J. Converse - updated: 9/18/2007
Victor A. McKusick - updated: 2/21/2007
Paul J. Converse - updated: 4/19/2006
Paul J. Converse - updated: 3/14/2006
Paul J. Converse - updated: 2/14/2006
Natalie E. Krasikov - updated: 8/10/2004
Ada Hamosh - updated: 4/3/2003
*FIELD* CD
Paul J. Converse: 4/25/2002
*FIELD* ED
mgross: 03/01/2011
terry: 2/28/2011
mgross: 2/4/2011
terry: 12/20/2010
alopez: 7/2/2010
terry: 7/1/2010
mgross: 1/29/2009
terry: 1/29/2009
mgross: 10/25/2007
terry: 9/18/2007
alopez: 2/26/2007
terry: 2/21/2007
mgross: 4/19/2006
mgross: 3/14/2006
mgross: 2/16/2006
terry: 2/14/2006
carol: 2/14/2006
terry: 8/10/2004
joanna: 4/10/2003
alopez: 4/7/2003
terry: 4/3/2003
mgross: 4/25/2002
MIM
607676
*RECORD*
*FIELD* NO
607676
*FIELD* TI
#607676 IRAK4 DEFICIENCY
;;IRAK4D
*FIELD* TX
A number sign (#) is used with this entry because IRAK4 deficiency is
read morecaused by homozygous or compound heterozygous mutation in the gene
encoding interleukin-1 receptor-associated kinase-4 (IRAK4; 606883).
DESCRIPTION
IRAK4 deficiency is an autosomal recessive primary immunodeficiency that
impairs Toll (see TLR4; 603030)/IL1R (see IL1R1; 147810) immunity,
except for the TLR3 (603029)- and TLR4-interferon-alpha (IFNA;
147660)/beta (IFNB; 147640) pathways (Ku et al., 2007).
CLINICAL FEATURES
Picard et al. (2003) described 3 unrelated children with recurrent
infections and poor inflammatory response in whom extracellular,
pyogenic bacteria were the only microorganisms responsible for
infection. Gram-positive Streptococcus pneumoniae and Staphylococcus
aureus were the most frequently found and were the only pathogens
identified in 2 patients. Infections began early in life but became less
frequent with age, and the patients were well with no treatment at ages
6, 11, and 7 years. All known primary immunodeficiencies were excluded.
In particular, the patients had normal serum antibody titers against
protein and polysaccharide antigens, including those from S. pneumoniae.
However, 1 of the 3 patients had been shown not to respond to
lipopolysaccharide (LPS) or S. aureus (Haraguchi et al., 1998). None of
the patients' monocytes responded to LPS; however, they responded
normally to TNF-alpha (191160). The patients did not respond to IL1-beta
(147720), IL18 (600953), or any of the TLR1-6 (see 601194) or TLR9
(605474) ligands, as assessed by activation of NF-kappa-B (see 164011)
and p38-MAPK (600289) and induction of IL1-beta, IL6 (147620), IL12 (see
161561), TNF-alpha, and IFNG (147570).
In a follow-up of the patients reported by Picard et al. (2003), Day et
al. (2004) found that 2 continued to do well, but 1, an 8-year-old girl,
was unable to sustain antibody responses to polysaccharide or protein
antigens or to a neoantigen-bacteriophage. She continued to have
recurring bacterial and fungal infections, eventually requiring
intravenous immunoglobulin therapy. They recommended testing for IRAK4
deficiency in patients with recurrent bacterial and fungal infections
without sustained antibody response to immunization.
Ku et al. (2007) tested TLR responses of whole blood and individual
leukocyte subsets in 28 patients with IRAK4 deficiency and found that
only the TLR3 agonist poly(I:C) could induce production of 11 non-IFN
cytokines. The TLR4 agonist, LPS, could induce some responses in myeloid
dendritic cells and monocyte-derived dendritic cells. Most patients
suffered from invasive and often recurrent pneumococcal disease, but
other infections, except for severe staphylococcal disease, were rare.
Nearly half of the patients died. Death occurred only in patients 8
years old and younger, and invasive disease occurred only in those 14
years old and younger. Ku et al. (2007) concluded that IRAK4-dependent
TLRs and IL1Rs are vital for childhood immunity to pyogenic bacteria,
particularly S. pneumoniae, but they are not essential for protective
immunity to most infections.
Hoarau et al. (2007) investigated a 14-year-old French boy of healthy,
unrelated patients with IRAK4 deficiency characterized by recurrent
infections, osteomyelitis, and cellulitis beginning at age 15 days.
Apart from elevated C-reactive protein (CRP; 123260) and very low
polymorphonuclear neutrophil (PMN) numbers, his immunologic status was
normal. Hoarau et al. (2007) found that the patient was compound
heterozygous for 2 mutations in the IRAK4 gene (see 606883.0006 and
606883.0007). Stimulation of the patient's PMNs with TLR agonists
revealed the absence of IRAK1 (300283) phosphorylation and impaired PMN
responses. However, responses to the TLR9 agonist CpG were normal,
except for cytokine production. Impairment of TLR9 responses was
observed after pretreatment with PI3K (see 601232) inhibitors. Hoarau et
al. (2007) proposed that there may be an alternative TLR9 pathway
leading to PI3K activation independently of the classical MYD88
(602170)-IRAK4 pathway. They suggested that this alternative pathway may
play a role in control of infections by microorganisms other than
pyogenic bacteria in patients with IRAK4 deficiency.
MOLECULAR GENETICS
Picard et al. (2003) found that all 3 patients with pyogenic bacterial
infections were homozygous for a mutation in the IRAK4 gene (see
606883.0001-606883.0002) and that in each case the mutations were
associated with complete deficiency for the kinase.
PATHOGENESIS
By studying responses to the TLR4 ligand, LPS, and to the bacterial
chemoattractant, fMLP, in PMNs from 1 patient with IRAK4 deficiency and
3 patients with NEMO (300248) deficiency causing X-linked hyper-IgM
immunodeficiency with ectodermal dysplasia (300291), Singh et al. (2009)
demonstrated reduced or absent superoxide production after impaired
priming and activation of the oligomeric neutrophil NADPH oxidase (NOX;
see 300481). The response was particularly weak or absent in
IRAK4-deficient PMNs. NEMO-deficient PMNs had a phenotype intermediate
between IRAK4-deficient PMNs and normal PMNs. Decreased LPS- and
fMLP-induced phosphorylation of p38 (MAPK14; 600289) was observed in
both deficiencies. Singh et al. (2009) proposed that decreased
activation of NOX may contribute to increased risk of infection in
patients with IRAK4 deficiency or NEMO deficiency.
*FIELD* RF
1. Day, N.; Tangsinmankong, N.; Ochs, H.; Rucker, R.; Picard, C.;
Casanova, J.-L.; Haraguchi, S.; Good, R.: Interleukin receptor-associated
kinase (IRAK-4) deficiency associated with bacterial infections and
failure to sustain antibody responses. J. Pediat. 144: 524-526,
2004.
2. Haraguchi, S.; Day, N. K.; Nelson, R. P., Jr.; Emmanuel, P.; Duplantier,
J. E.; Christodoulou, C. S.; Good, R. A.: Interleukin 12 deficiency
associated with recurrent infections. Proc. Nat. Acad. Sci. 95:
13125-13129, 1998.
3. Hoarau, C.; Gerard, B.; Lescanne, E.; Henry, D.; Francois, S.;
Lacapere, J.-J.; El Benna, J.; Dang, P. M.-C.; Grandchamp, B.; Lebranchu,
Y.; Gougerot-Pocidalo, M.-A.; Elbim, C.: TLR9 activation induces
normal neutrophil responses in a child with IRAK-4 deficiency: involvement
of the direct PI3K pathway. J. Immun. 179: 4754-4765, 2007.
4. Ku, C.-L.; von Bernuth, H.; Picard, C.; Zhang, S.-Y.; Chang, H.-H.;
Yang, K.; Chrabieh, M.; Issekutz, A. C.; Cunningham, C. K.; Gallin,
J.; Holland, S. M.; Roifman, C.; and 25 others: Selective predisposition
to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent
TLRs are otherwise redundant in protective immunity. J. Exp. Med. 204:
2407-2422, 2007.
5. Picard, C.; Puel, A.; Bonnet, M.; Ku, C.-L.; Bustamante, J.; Yang,
K.; Soudais, C.; Dupuis, S.; Feinberg, J.; Fieschi, C.; Elbim, C.;
Hitchcock, R.; and 18 others: Pyogenic bacterial infections in
humans with IRAK-4 deficiency. Science 299: 2076-2079, 2003.
6. Singh, A.; Zarember, K. A.; Kuhns, D. B.; Gallin, J. I.: Impaired
priming and activation of the neutrophil NADPH oxidase in patients
with IRAK4 or NEMO deficiency. J. Immun. 182: 6410-6417, 2009.
*FIELD* CN
Paul J. Converse - updated: 3/1/2011
Paul J. Converse - updated: 2/4/2011
Matthew B. Gross - updated: 1/29/2009
Paul J. Converse - updated: 1/29/2009
Natalie E. Krasikov - updated: 8/10/2004
*FIELD* CD
Ada Hamosh: 4/7/2003
*FIELD* ED
carol: 06/22/2011
mgross: 3/1/2011
mgross: 2/4/2011
mgross: 1/29/2009
carol: 8/10/2004
terry: 8/10/2004
alopez: 4/7/2003
*RECORD*
*FIELD* NO
607676
*FIELD* TI
#607676 IRAK4 DEFICIENCY
;;IRAK4D
*FIELD* TX
A number sign (#) is used with this entry because IRAK4 deficiency is
read morecaused by homozygous or compound heterozygous mutation in the gene
encoding interleukin-1 receptor-associated kinase-4 (IRAK4; 606883).
DESCRIPTION
IRAK4 deficiency is an autosomal recessive primary immunodeficiency that
impairs Toll (see TLR4; 603030)/IL1R (see IL1R1; 147810) immunity,
except for the TLR3 (603029)- and TLR4-interferon-alpha (IFNA;
147660)/beta (IFNB; 147640) pathways (Ku et al., 2007).
CLINICAL FEATURES
Picard et al. (2003) described 3 unrelated children with recurrent
infections and poor inflammatory response in whom extracellular,
pyogenic bacteria were the only microorganisms responsible for
infection. Gram-positive Streptococcus pneumoniae and Staphylococcus
aureus were the most frequently found and were the only pathogens
identified in 2 patients. Infections began early in life but became less
frequent with age, and the patients were well with no treatment at ages
6, 11, and 7 years. All known primary immunodeficiencies were excluded.
In particular, the patients had normal serum antibody titers against
protein and polysaccharide antigens, including those from S. pneumoniae.
However, 1 of the 3 patients had been shown not to respond to
lipopolysaccharide (LPS) or S. aureus (Haraguchi et al., 1998). None of
the patients' monocytes responded to LPS; however, they responded
normally to TNF-alpha (191160). The patients did not respond to IL1-beta
(147720), IL18 (600953), or any of the TLR1-6 (see 601194) or TLR9
(605474) ligands, as assessed by activation of NF-kappa-B (see 164011)
and p38-MAPK (600289) and induction of IL1-beta, IL6 (147620), IL12 (see
161561), TNF-alpha, and IFNG (147570).
In a follow-up of the patients reported by Picard et al. (2003), Day et
al. (2004) found that 2 continued to do well, but 1, an 8-year-old girl,
was unable to sustain antibody responses to polysaccharide or protein
antigens or to a neoantigen-bacteriophage. She continued to have
recurring bacterial and fungal infections, eventually requiring
intravenous immunoglobulin therapy. They recommended testing for IRAK4
deficiency in patients with recurrent bacterial and fungal infections
without sustained antibody response to immunization.
Ku et al. (2007) tested TLR responses of whole blood and individual
leukocyte subsets in 28 patients with IRAK4 deficiency and found that
only the TLR3 agonist poly(I:C) could induce production of 11 non-IFN
cytokines. The TLR4 agonist, LPS, could induce some responses in myeloid
dendritic cells and monocyte-derived dendritic cells. Most patients
suffered from invasive and often recurrent pneumococcal disease, but
other infections, except for severe staphylococcal disease, were rare.
Nearly half of the patients died. Death occurred only in patients 8
years old and younger, and invasive disease occurred only in those 14
years old and younger. Ku et al. (2007) concluded that IRAK4-dependent
TLRs and IL1Rs are vital for childhood immunity to pyogenic bacteria,
particularly S. pneumoniae, but they are not essential for protective
immunity to most infections.
Hoarau et al. (2007) investigated a 14-year-old French boy of healthy,
unrelated patients with IRAK4 deficiency characterized by recurrent
infections, osteomyelitis, and cellulitis beginning at age 15 days.
Apart from elevated C-reactive protein (CRP; 123260) and very low
polymorphonuclear neutrophil (PMN) numbers, his immunologic status was
normal. Hoarau et al. (2007) found that the patient was compound
heterozygous for 2 mutations in the IRAK4 gene (see 606883.0006 and
606883.0007). Stimulation of the patient's PMNs with TLR agonists
revealed the absence of IRAK1 (300283) phosphorylation and impaired PMN
responses. However, responses to the TLR9 agonist CpG were normal,
except for cytokine production. Impairment of TLR9 responses was
observed after pretreatment with PI3K (see 601232) inhibitors. Hoarau et
al. (2007) proposed that there may be an alternative TLR9 pathway
leading to PI3K activation independently of the classical MYD88
(602170)-IRAK4 pathway. They suggested that this alternative pathway may
play a role in control of infections by microorganisms other than
pyogenic bacteria in patients with IRAK4 deficiency.
MOLECULAR GENETICS
Picard et al. (2003) found that all 3 patients with pyogenic bacterial
infections were homozygous for a mutation in the IRAK4 gene (see
606883.0001-606883.0002) and that in each case the mutations were
associated with complete deficiency for the kinase.
PATHOGENESIS
By studying responses to the TLR4 ligand, LPS, and to the bacterial
chemoattractant, fMLP, in PMNs from 1 patient with IRAK4 deficiency and
3 patients with NEMO (300248) deficiency causing X-linked hyper-IgM
immunodeficiency with ectodermal dysplasia (300291), Singh et al. (2009)
demonstrated reduced or absent superoxide production after impaired
priming and activation of the oligomeric neutrophil NADPH oxidase (NOX;
see 300481). The response was particularly weak or absent in
IRAK4-deficient PMNs. NEMO-deficient PMNs had a phenotype intermediate
between IRAK4-deficient PMNs and normal PMNs. Decreased LPS- and
fMLP-induced phosphorylation of p38 (MAPK14; 600289) was observed in
both deficiencies. Singh et al. (2009) proposed that decreased
activation of NOX may contribute to increased risk of infection in
patients with IRAK4 deficiency or NEMO deficiency.
*FIELD* RF
1. Day, N.; Tangsinmankong, N.; Ochs, H.; Rucker, R.; Picard, C.;
Casanova, J.-L.; Haraguchi, S.; Good, R.: Interleukin receptor-associated
kinase (IRAK-4) deficiency associated with bacterial infections and
failure to sustain antibody responses. J. Pediat. 144: 524-526,
2004.
2. Haraguchi, S.; Day, N. K.; Nelson, R. P., Jr.; Emmanuel, P.; Duplantier,
J. E.; Christodoulou, C. S.; Good, R. A.: Interleukin 12 deficiency
associated with recurrent infections. Proc. Nat. Acad. Sci. 95:
13125-13129, 1998.
3. Hoarau, C.; Gerard, B.; Lescanne, E.; Henry, D.; Francois, S.;
Lacapere, J.-J.; El Benna, J.; Dang, P. M.-C.; Grandchamp, B.; Lebranchu,
Y.; Gougerot-Pocidalo, M.-A.; Elbim, C.: TLR9 activation induces
normal neutrophil responses in a child with IRAK-4 deficiency: involvement
of the direct PI3K pathway. J. Immun. 179: 4754-4765, 2007.
4. Ku, C.-L.; von Bernuth, H.; Picard, C.; Zhang, S.-Y.; Chang, H.-H.;
Yang, K.; Chrabieh, M.; Issekutz, A. C.; Cunningham, C. K.; Gallin,
J.; Holland, S. M.; Roifman, C.; and 25 others: Selective predisposition
to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent
TLRs are otherwise redundant in protective immunity. J. Exp. Med. 204:
2407-2422, 2007.
5. Picard, C.; Puel, A.; Bonnet, M.; Ku, C.-L.; Bustamante, J.; Yang,
K.; Soudais, C.; Dupuis, S.; Feinberg, J.; Fieschi, C.; Elbim, C.;
Hitchcock, R.; and 18 others: Pyogenic bacterial infections in
humans with IRAK-4 deficiency. Science 299: 2076-2079, 2003.
6. Singh, A.; Zarember, K. A.; Kuhns, D. B.; Gallin, J. I.: Impaired
priming and activation of the neutrophil NADPH oxidase in patients
with IRAK4 or NEMO deficiency. J. Immun. 182: 6410-6417, 2009.
*FIELD* CN
Paul J. Converse - updated: 3/1/2011
Paul J. Converse - updated: 2/4/2011
Matthew B. Gross - updated: 1/29/2009
Paul J. Converse - updated: 1/29/2009
Natalie E. Krasikov - updated: 8/10/2004
*FIELD* CD
Ada Hamosh: 4/7/2003
*FIELD* ED
carol: 06/22/2011
mgross: 3/1/2011
mgross: 2/4/2011
mgross: 1/29/2009
carol: 8/10/2004
terry: 8/10/2004
alopez: 4/7/2003
MIM
610799
*RECORD*
*FIELD* NO
610799
*FIELD* TI
#610799 INVASIVE PNEUMOCOCCAL DISEASE, RECURRENT ISOLATED, 1; IPD1
INVASIVE PNEUMOCOCCAL DISEASE, PROTECTION AGAINST, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because recurrent isolated
invasive pneumococcal disease (IPD1) can be caused by mutation in the
IRAK4 gene (606883). Another form of this disorder (IPD2; 300640) is
caused by mutation in the NEMO gene (300248). Protection against IPD has
been associated with a coding single-nucleotide polymorphism (SNP) in
the TIRAP gene (606252.0001).
DESCRIPTION
Recurrent invasive pneumococcal disease (IPD) is defined as 2 episodes
of IPD occurring at least 1 month apart, whether caused by the same or
different serotypes or strains (Ku et al., 2007). Recurrent IPD occurs
in at least 2% of patients in most series, making IPD the most important
known risk factor for subsequent IPD.
CLINICAL FEATURES
Ku et al. (2007) described 2 otherwise healthy children with isolated
recurrent IPD as the only clinical infectious manifestation of an
inherited disorder in nuclear factor kappa-B (see 164011)-dependent
immunity. One was found to carry a hemizygous mutation in the NEMO gene
(see IPD2, 300640). The other was a 7-year-old boy born to unrelated
Hungarian parents. He received immunizations with no complications. At
age 3 years, he developed arthritis of the right hip caused by
Streptococcus pneumoniae serotype 14. He was successfully treated with
intravenous antibiotic for 12 days. At age 5.5 years, he developed
meningitis caused by Streptococcus pneumoniae serotype 14, with moderate
headache and a slightly high temperature. The patient recovered without
sequelae after treatment for 12 days with intravenous antibiotic. He had
no other bacterial, viral, or fungal disease. Poor clinical and biologic
inflammatory responses during infectious episodes and antipolysaccharide
antibody deficiency suggested genetic defects in Toll-like receptor
(TLR) (see 603030)-NF-kappa-B-mediated immunity. Fibroblasts showed no
response to interleukin-1-beta (147720), but normal responses to
TNF-alpha (191160), stimulation; overall, responses suggested a defect
in TLR and IL1R signaling pathways. He was immunized with the
heptavalent pneumococcal conjugate vaccine and with a 23-valent
pneumococcal vaccine, and prescribed monthly intravenous immunoglobulin
infusions. He remained well with no further infections to the time of
the report.
MOLECULAR GENETICS
In a 7-year-old boy born of unrelated Hungarian parents, Ku et al.
(2007) found that recurrent invasive pneumococcal disease (IPD1; 610799)
was related to compound heterozygosity for 2 mutations in the IRAK4
gene, located in the intron between exons 10 and 11: 1189-1G-T and
1188+520A-G (606883.0005). The authors noted that this patient was the
first in whom noncoding mutation in the IRAK4 gene had been found.
Autosomal recessive IRAK4 deficiency (607676) and X-linked recessive
NEMO deficiencies (e.g., 300291, 300584) are primary immunodeficiencies
that affect NF-kappa-B-mediated immunity and cause a relatively broad
susceptibility to infections. The patients described by Ku et al. (2007)
displayed none of the other known infectious phenotypes associated with
these disorders.
Khor et al. (2007) found that heterozygous carriage of a leucine
substitution at ser180 of the TIRAP gene (606252.0001) associated
independently with protection against 4 infectious diseases, including
invasive pneumococcal disease, in several different study populations.
*FIELD* RF
1. Khor, C. C.; Chapman, S. J.; Vannberg, F. O.; Dunne, A.; Murphy,
C.; Ling, E. Y.; Frodsham, A. J.; Walley, A. J.; Kyrieleis, O.; Khan,
A.; Aucan, C.; Segal, S.; and 22 others: A Mal functional variant
is associated with protection against invasive pneumococcal disease,
bacteremia, malaria and tuberculosis. Nature Genet. 39: 523-528,
2007.
2. Ku, C.-L.; Picard, C.; Erdos, M.; Jeurissen, A.; Bustamante, J.;
Puel, A.; von Bernuth, H.; Filipe-Santos, O.; Chang, H.-H.; Lawrence,
T.; Raes, M.; Marodi, L.; Bossuyt, X.; Casanova, J.-L.: IRAK4 and
NEMO mutations in otherwise healthy children with recurrent invasive
pneumococcal disease. J. Med. Genet. 44: 16-23, 2007.
*FIELD* CD
Victor A. McKusick: 2/26/2007
*FIELD* ED
alopez: 06/28/2007
alopez: 6/13/2007
alopez: 2/26/2007
*RECORD*
*FIELD* NO
610799
*FIELD* TI
#610799 INVASIVE PNEUMOCOCCAL DISEASE, RECURRENT ISOLATED, 1; IPD1
INVASIVE PNEUMOCOCCAL DISEASE, PROTECTION AGAINST, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because recurrent isolated
invasive pneumococcal disease (IPD1) can be caused by mutation in the
IRAK4 gene (606883). Another form of this disorder (IPD2; 300640) is
caused by mutation in the NEMO gene (300248). Protection against IPD has
been associated with a coding single-nucleotide polymorphism (SNP) in
the TIRAP gene (606252.0001).
DESCRIPTION
Recurrent invasive pneumococcal disease (IPD) is defined as 2 episodes
of IPD occurring at least 1 month apart, whether caused by the same or
different serotypes or strains (Ku et al., 2007). Recurrent IPD occurs
in at least 2% of patients in most series, making IPD the most important
known risk factor for subsequent IPD.
CLINICAL FEATURES
Ku et al. (2007) described 2 otherwise healthy children with isolated
recurrent IPD as the only clinical infectious manifestation of an
inherited disorder in nuclear factor kappa-B (see 164011)-dependent
immunity. One was found to carry a hemizygous mutation in the NEMO gene
(see IPD2, 300640). The other was a 7-year-old boy born to unrelated
Hungarian parents. He received immunizations with no complications. At
age 3 years, he developed arthritis of the right hip caused by
Streptococcus pneumoniae serotype 14. He was successfully treated with
intravenous antibiotic for 12 days. At age 5.5 years, he developed
meningitis caused by Streptococcus pneumoniae serotype 14, with moderate
headache and a slightly high temperature. The patient recovered without
sequelae after treatment for 12 days with intravenous antibiotic. He had
no other bacterial, viral, or fungal disease. Poor clinical and biologic
inflammatory responses during infectious episodes and antipolysaccharide
antibody deficiency suggested genetic defects in Toll-like receptor
(TLR) (see 603030)-NF-kappa-B-mediated immunity. Fibroblasts showed no
response to interleukin-1-beta (147720), but normal responses to
TNF-alpha (191160), stimulation; overall, responses suggested a defect
in TLR and IL1R signaling pathways. He was immunized with the
heptavalent pneumococcal conjugate vaccine and with a 23-valent
pneumococcal vaccine, and prescribed monthly intravenous immunoglobulin
infusions. He remained well with no further infections to the time of
the report.
MOLECULAR GENETICS
In a 7-year-old boy born of unrelated Hungarian parents, Ku et al.
(2007) found that recurrent invasive pneumococcal disease (IPD1; 610799)
was related to compound heterozygosity for 2 mutations in the IRAK4
gene, located in the intron between exons 10 and 11: 1189-1G-T and
1188+520A-G (606883.0005). The authors noted that this patient was the
first in whom noncoding mutation in the IRAK4 gene had been found.
Autosomal recessive IRAK4 deficiency (607676) and X-linked recessive
NEMO deficiencies (e.g., 300291, 300584) are primary immunodeficiencies
that affect NF-kappa-B-mediated immunity and cause a relatively broad
susceptibility to infections. The patients described by Ku et al. (2007)
displayed none of the other known infectious phenotypes associated with
these disorders.
Khor et al. (2007) found that heterozygous carriage of a leucine
substitution at ser180 of the TIRAP gene (606252.0001) associated
independently with protection against 4 infectious diseases, including
invasive pneumococcal disease, in several different study populations.
*FIELD* RF
1. Khor, C. C.; Chapman, S. J.; Vannberg, F. O.; Dunne, A.; Murphy,
C.; Ling, E. Y.; Frodsham, A. J.; Walley, A. J.; Kyrieleis, O.; Khan,
A.; Aucan, C.; Segal, S.; and 22 others: A Mal functional variant
is associated with protection against invasive pneumococcal disease,
bacteremia, malaria and tuberculosis. Nature Genet. 39: 523-528,
2007.
2. Ku, C.-L.; Picard, C.; Erdos, M.; Jeurissen, A.; Bustamante, J.;
Puel, A.; von Bernuth, H.; Filipe-Santos, O.; Chang, H.-H.; Lawrence,
T.; Raes, M.; Marodi, L.; Bossuyt, X.; Casanova, J.-L.: IRAK4 and
NEMO mutations in otherwise healthy children with recurrent invasive
pneumococcal disease. J. Med. Genet. 44: 16-23, 2007.
*FIELD* CD
Victor A. McKusick: 2/26/2007
*FIELD* ED
alopez: 06/28/2007
alopez: 6/13/2007
alopez: 2/26/2007