Full text data of FADD
FADD
(MORT1)
[Confidence: low (only semi-automatic identification from reviews)]
Protein FADD (FAS-associated death domain protein; FAS-associating death domain-containing protein; Growth-inhibiting gene 3 protein; Mediator of receptor induced toxicity)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Protein FADD (FAS-associated death domain protein; FAS-associating death domain-containing protein; Growth-inhibiting gene 3 protein; Mediator of receptor induced toxicity)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q13158
ID FADD_HUMAN Reviewed; 208 AA.
AC Q13158; Q14866; Q6IBR4;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1997, sequence version 1.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=Protein FADD;
DE AltName: Full=FAS-associated death domain protein;
DE AltName: Full=FAS-associating death domain-containing protein;
DE AltName: Full=Growth-inhibiting gene 3 protein;
DE AltName: Full=Mediator of receptor induced toxicity;
GN Name=FADD; Synonyms=MORT1; ORFNames=GIG3;
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], AND MUTAGENESIS.
RC TISSUE=Umbilical vein endothelial cell;
RX PubMed=7538907; DOI=10.1016/0092-8674(95)90071-3;
RA Chinnaiyan A.M., O'Rourke K., Tewari M., Dixit V.M.;
RT "FADD, a novel death domain-containing protein, interacts with the
RT death domain of Fas and initiates apoptosis.";
RL Cell 81:505-512(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7536190; DOI=10.1074/jbc.270.14.7795;
RA Boldin M.P., Varfolomeev E.E., Pancer Z., Mett I.L., Camonis J.H.,
RA Wallach D.;
RT "A novel protein that interacts with the death domain of Fas/APO1
RT contains a sequence motif related to the death domain.";
RL J. Biol. Chem. 270:7795-7798(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kim J.W.;
RT "Identification of a human growth inhibition gene 3 (GIG3).";
RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (MAR-2006) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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 [10]
RP INTERACTION WITH PEA15.
RX PubMed=10442631; DOI=10.1038/sj.onc.1202831;
RA Condorelli G., Vigliotta G., Cafieri A., Trencia A., Andalo P.,
RA Oriente F., Miele C., Caruso M., Formisano P., Beguinot F.;
RT "PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-
RT induced apoptosis.";
RL Oncogene 18:4409-4415(1999).
RN [11]
RP INTERACTION WITH LRDD.
RX PubMed=10825539; DOI=10.1016/S0167-4838(00)00029-7;
RA Telliez J.-B., Bean K.M., Lin L.-L.;
RT "LRDD, a novel leucine rich repeat and death domain containing
RT protein.";
RL Biochim. Biophys. Acta 1478:280-288(2000).
RN [12]
RP IDENTIFICATION IN A COMPLEX WITH HIPK3 AND FAS, AND PHOSPHORYLATION AT
RP SER-194.
RX PubMed=11034606; DOI=10.1084/jem.192.8.1165;
RA Rochat-Steiner V., Becker K., Micheau O., Schneider P., Burns K.,
RA Tschopp J.;
RT "FIST/HIPK3: a Fas/FADD-interacting serine/threonine kinase that
RT induces FADD phosphorylation and inhibits Fas-mediated Jun NH2-
RT terminal kinase activation.";
RL J. Exp. Med. 192:1165-1174(2000).
RN [13]
RP INTERACTION WITH MBD4.
RX PubMed=12702765; DOI=10.1073/pnas.0431215100;
RA Screaton R.A., Kiessling S., Sansom O.J., Millar C.B., Maddison K.,
RA Bird A., Clarke A.R., Frisch S.M.;
RT "Fas-associated death domain protein interacts with methyl-CpG binding
RT domain protein 4: a potential link between genome surveillance and
RT apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:5211-5216(2003).
RN [14]
RP INTERACTION WITH MAVS.
RX PubMed=16127453; DOI=10.1038/ni1243;
RA Kawai T., Takahashi K., Sato S., Coban C., Kumar H., Kato H.,
RA Ishii K.J., Takeuchi O., Akira S.;
RT "IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I
RT interferon induction.";
RL Nat. Immunol. 6:981-988(2005).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-194, AND MASS
RP SPECTROMETRY.
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 [17]
RP FUNCTION IN INTERFERON-MEDIATED IMMUNITY, INTERACTION WITH FAS,
RP VARIANT IEHDCM TRP-105, AND CHARACTERIZATION OF VARIANT IEHDCM
RP TRP-105.
RX PubMed=21109225; DOI=10.1016/j.ajhg.2010.10.028;
RA Bolze A., Byun M., McDonald D., Morgan N.V., Abhyankar A.,
RA Premkumar L., Puel A., Bacon C.M., Rieux-Laucat F., Pang K.,
RA Britland A., Abel L., Cant A., Maher E.R., Riedl S.J., Hambleton S.,
RA Casanova J.L.;
RT "Whole-exome-sequencing-based discovery of human FADD deficiency.";
RL Am. J. Hum. Genet. 87:873-881(2010).
RN [18]
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 [19]
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 [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-194, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [21]
RP STRUCTURE BY NMR OF 1-83.
RX PubMed=9582077; DOI=10.1038/31972;
RA Eberstadt M., Huang B., Chen Z., Meadows R.P., Ng S.C., Zheng L.,
RA Lenardo M.J., Fesik S.W.;
RT "NMR structure and mutagenesis of the FADD (Mort1) death-effector
RT domain.";
RL Nature 392:941-945(1998).
RN [22]
RP STRUCTURE BY NMR OF 93-192.
RX PubMed=10964568; DOI=10.1006/jmbi.2000.4011;
RA Berglund H., Olerenshaw D., Sankar A., Federwisch M., McDonald N.Q.,
RA Driscoll P.C.;
RT "The three-dimensional solution structure and dynamic properties of
RT the human FADD death domain.";
RL J. Mol. Biol. 302:171-188(2000).
RN [23]
RP STRUCTURE BY NMR OF 2-191, FUNCTION, INTERACTION WITH FAS AND CASP8,
RP AND MUTAGENESIS OF SER-12; PHE-25; LYS-33; ARG-38; ASP-44 AND GLU-51.
RX PubMed=16762833; DOI=10.1016/j.molcel.2006.04.018;
RA Carrington P.E., Sandu C., Wei Y., Hill J.M., Morisawa G., Huang T.,
RA Gavathiotis E., Wei Y., Werner M.H.;
RT "The structure of FADD and its mode of interaction with procaspase-
RT 8.";
RL Mol. Cell 22:599-610(2006).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.73 ANGSTROMS) OF 93-208 IN COMPLEX WITH FAS,
RP FUNCTION, SUBUNIT, ELECTRON MICROSCOPY, DOMAIN, AND MUTAGENESIS OF
RP LEU-172 AND LEU-176.
RX PubMed=19118384; DOI=10.1038/nature07606;
RA Scott F.L., Stec B., Pop C., Dobaczewska M.K., Lee J.J., Monosov E.,
RA Robinson H., Salvesen G.S., Schwarzenbacher R., Riedl S.J.;
RT "The Fas-FADD death domain complex structure unravels signalling by
RT receptor clustering.";
RL Nature 457:1019-1022(2009).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (6.80 ANGSTROMS) OF 93-184 IN COMPLEX WITH FAS,
RP ELECTRON MICROSCOPY, FUNCTION, MASS SPECTROMETRY, SUBUNIT, AND
RP MUTAGENESIS OF ARG-117; ASP-123; ARG-135; ARG-142; LEU-172 AND
RP ASP-175.
RX PubMed=20935634; DOI=10.1038/nsmb.1920;
RA Wang L., Yang J.K., Kabaleeswaran V., Rice A.J., Cruz A.C., Park A.Y.,
RA Yin Q., Damko E., Jang S.B., Raunser S., Robinson C.V., Siegel R.M.,
RA Walz T., Wu H.;
RT "The Fas-FADD death domain complex structure reveals the basis of DISC
RT assembly and disease mutations.";
RL Nat. Struct. Mol. Biol. 17:1324-1329(2010).
CC -!- FUNCTION: Apoptotic adaptor molecule that recruits caspase-8 or
CC caspase-10 to the activated Fas (CD95) or TNFR-1 receptors. The
CC resulting aggregate called the death-inducing signaling complex
CC (DISC) performs caspase-8 proteolytic activation. Active caspase-8
CC initiates the subsequent cascade of caspases mediating apoptosis.
CC Involved in interferon-mediated antiviral immune response, playing
CC a role in the positive regulation of interferon signaling.
CC -!- SUBUNIT: Can self-associate. Interacts with CFLAR, PEA15 and MBD4.
CC When phosphorylated, part of a complex containing HIPK3 and FAS.
CC May interact with MAVS/IPS1. Interacts with MOCV v-CFLAR protein
CC and LRDD. Interacts (via death domain) with FAS (via death
CC domain). Interacts with CASP8.
CC -!- INTERACTION:
CC Self; NbExp=3; IntAct=EBI-494804, EBI-494804;
CC Q14790:CASP8; NbExp=32; IntAct=EBI-494804, EBI-78060;
CC Q14790-1:CASP8; NbExp=5; IntAct=EBI-494804, EBI-288309;
CC Q14790-5:CASP8; NbExp=4; IntAct=EBI-494804, EBI-288326;
CC P25445:FAS; NbExp=32; IntAct=EBI-494804, EBI-494743;
CC P25446:Fas (xeno); NbExp=5; IntAct=EBI-494804, EBI-296206;
CC P48023:FASLG; NbExp=2; IntAct=EBI-494804, EBI-495538;
CC Q5S007:LRRK2; NbExp=4; IntAct=EBI-494804, EBI-5323863;
CC O95243:MBD4; NbExp=6; IntAct=EBI-494804, EBI-348011;
CC Q99836:MYD88; NbExp=3; IntAct=EBI-494804, EBI-447677;
CC Q99497:PARK7; NbExp=9; IntAct=EBI-494804, EBI-1164361;
CC P53350:PLK1; NbExp=9; IntAct=EBI-494804, EBI-476768;
CC Q13546:RIPK1; NbExp=5; IntAct=EBI-494804, EBI-358507;
CC -!- TISSUE SPECIFICITY: Expressed in a wide variety of tissues, except
CC for peripheral blood mononuclear leukocytes.
CC -!- DOMAIN: Contains a death domain involved in the binding of the
CC corresponding domain within Fas receptor.
CC -!- DOMAIN: The interaction between the FAS and FADD death domains is
CC crucial for the formation of the death-inducing signaling complex
CC (DISC).
CC -!- DISEASE: Infections, recurrent, associated with encephalopathy,
CC hepatic dysfunction and cardiovascular malformations (IEHDCM)
CC [MIM:613759]: A condition with biological features of autoimmune
CC lymphoproliferative syndrome such as high-circulating
CC CD4(-)CD8(-)TCR-alpha-beta(+) T-cell counts, and elevated IL10 and
CC FASL levels. Affected individuals suffer from recurrent,
CC stereotypical episodes of fever, encephalopathy, and mild liver
CC dysfunction sometimes accompanied by generalized seizures. The
CC episodes can be triggered by varicella zoster virus (VZV), measles
CC mumps rubella (MMR) attenuated vaccine, parainfluenza virus, and
CC Epstein-Barr virus (EBV). Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 death domain.
CC -!- SIMILARITY: Contains 1 DED (death effector) domain.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/fadd/";
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DR EMBL; U24231; AAA86517.1; -; mRNA.
DR EMBL; X84709; CAA59197.1; -; mRNA.
DR EMBL; AY423721; AAS00484.1; -; mRNA.
DR EMBL; AK291005; BAF83694.1; -; mRNA.
DR EMBL; BT006927; AAP35573.1; -; mRNA.
DR EMBL; CR456738; CAG33019.1; -; mRNA.
DR EMBL; DQ449938; ABD96828.1; -; Genomic_DNA.
DR EMBL; CH471076; EAW74761.1; -; Genomic_DNA.
DR EMBL; BC000334; AAH00334.1; -; mRNA.
DR PIR; A56912; A56912.
DR RefSeq; NP_003815.1; NM_003824.3.
DR UniGene; Hs.86131; -.
DR PDB; 1A1W; NMR; -; A=1-83.
DR PDB; 1A1Z; NMR; -; A=1-83.
DR PDB; 1E3Y; NMR; -; A=93-192.
DR PDB; 1E41; NMR; -; A=93-192.
DR PDB; 2GF5; NMR; -; A=2-191.
DR PDB; 3EZQ; X-ray; 2.73 A; B/D/F/H/J/L/N/P=93-208.
DR PDB; 3OQ9; X-ray; 6.80 A; H/I/J/K/L=93-184.
DR PDBsum; 1A1W; -.
DR PDBsum; 1A1Z; -.
DR PDBsum; 1E3Y; -.
DR PDBsum; 1E41; -.
DR PDBsum; 2GF5; -.
DR PDBsum; 3EZQ; -.
DR PDBsum; 3OQ9; -.
DR ProteinModelPortal; Q13158; -.
DR SMR; Q13158; 2-191.
DR DIP; DIP-286N; -.
DR IntAct; Q13158; 27.
DR MINT; MINT-91814; -.
DR STRING; 9606.ENSP00000301838; -.
DR PhosphoSite; Q13158; -.
DR DMDM; 2498355; -.
DR PaxDb; Q13158; -.
DR PeptideAtlas; Q13158; -.
DR PRIDE; Q13158; -.
DR DNASU; 8772; -.
DR Ensembl; ENST00000301838; ENSP00000301838; ENSG00000168040.
DR GeneID; 8772; -.
DR KEGG; hsa:8772; -.
DR UCSC; uc001opm.2; human.
DR CTD; 8772; -.
DR GeneCards; GC11P070049; -.
DR HGNC; HGNC:3573; FADD.
DR HPA; CAB010209; -.
DR HPA; HPA001464; -.
DR MIM; 602457; gene.
DR MIM; 613759; phenotype.
DR neXtProt; NX_Q13158; -.
DR Orphanet; 306550; FADD-related immunodeficiency.
DR Orphanet; 99806; Oculootodental syndrome.
DR PharmGKB; PA27972; -.
DR eggNOG; NOG43830; -.
DR HOGENOM; HOG000112490; -.
DR HOVERGEN; HBG000853; -.
DR InParanoid; Q13158; -.
DR KO; K02373; -.
DR OMA; CQMNLVA; -.
DR OrthoDB; EOG76X61Z; -.
DR PhylomeDB; Q13158; -.
DR Reactome; REACT_578; Apoptosis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q13158; -.
DR EvolutionaryTrace; Q13158; -.
DR GeneWiki; FADD; -.
DR GenomeRNAi; 8772; -.
DR NextBio; 32890; -.
DR PRO; PR:Q13158; -.
DR ArrayExpress; Q13158; -.
DR Bgee; Q13158; -.
DR CleanEx; HS_FADD; -.
DR Genevestigator; Q13158; -.
DR GO; GO:0031265; C:CD95 death-inducing signaling complex; IDA:UniProtKB.
DR GO; GO:0044297; C:cell body; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR GO; GO:0097342; C:ripoptosome; IDA:UniProtKB.
DR GO; GO:0005123; F:death receptor binding; TAS:ProtInc.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:Reactome.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; IMP:UniProtKB.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; TAS:ProtInc.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0048535; P:lymph node development; ISS:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0070265; P:necrotic cell death; IMP:BHF-UCL.
DR GO; GO:0070236; P:negative regulation of activation-induced cell death of T cells; ISS:UniProtKB.
DR GO; GO:0042104; P:positive regulation of activated T cell proliferation; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:2000454; P:positive regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation; ISS:UniProtKB.
DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEP:UniProtKB.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; ISS:UniProtKB.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:BHF-UCL.
DR GO; GO:0045862; P:positive regulation of proteolysis; IDA:BHF-UCL.
DR GO; GO:0001916; P:positive regulation of T cell mediated cytotoxicity; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IDA:BHF-UCL.
DR GO; GO:0060340; P:positive regulation of type I interferon-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:2001239; P:regulation of extrinsic apoptotic signaling pathway in absence of ligand; TAS:Reactome.
DR GO; GO:0048536; P:spleen development; ISS:UniProtKB.
DR GO; GO:0033077; P:T cell differentiation in thymus; ISS:UniProtKB.
DR GO; GO:0043029; P:T cell homeostasis; ISS:UniProtKB.
DR GO; GO:0048538; P:thymus development; ISS:UniProtKB.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.533.10; -; 2.
DR InterPro; IPR011029; DEATH-like_dom.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR001875; DED.
DR InterPro; IPR016729; FADD.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF01335; DED; 1.
DR PIRSF; PIRSF018586; FADD; 1.
DR SMART; SM00005; DEATH; 1.
DR SMART; SM00031; DED; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR PROSITE; PS50017; DEATH_DOMAIN; 1.
DR PROSITE; PS50168; DED; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Apoptosis; Complete proteome; Disease mutation;
KW Host-virus interaction; Immunity; Innate immunity; Phosphoprotein;
KW Reference proteome.
FT CHAIN 1 208 Protein FADD.
FT /FTId=PRO_0000191279.
FT DOMAIN 3 81 DED.
FT DOMAIN 97 181 Death.
FT MOD_RES 194 194 Phosphoserine.
FT VARIANT 105 105 C -> W (in IEHDCM; reduced folding
FT stability as measured by differential
FT scanning calorimetry of the mutant
FT protein; impairs interaction with FAS).
FT /FTId=VAR_065124.
FT MUTAGEN 12 12 S->R: Loss of interaction with CASP8.
FT MUTAGEN 25 25 F->R: Loss of interaction with FAS. Loss
FT of self-association. Abolishes induction
FT of apoptosis.
FT MUTAGEN 33 33 K->E: Loss of self-association.
FT MUTAGEN 38 38 R->A: Loss of interaction with CASP8.
FT MUTAGEN 44 44 D->R: Loss of interaction with CASP8.
FT Abolishes induction of apoptosis.
FT Decreased interaction with FAS.
FT MUTAGEN 51 51 E->R: Loss of interaction with CASP8.
FT MUTAGEN 117 117 R->E: Loss of interaction with FAS.
FT MUTAGEN 121 121 V->N: Loss of interaction with FAS.
FT MUTAGEN 123 123 D->R: Strongly decreased interaction with
FT FAS.
FT MUTAGEN 135 135 R->E: Strongly decreased interaction with
FT FAS.
FT MUTAGEN 142 142 R->E: Decreased interaction with FAS.
FT MUTAGEN 172 172 L->A,E: Loss of interaction with FAS.
FT MUTAGEN 172 172 L->K: Strongly decreased interaction with
FT FAS.
FT MUTAGEN 175 175 D->K: Strongly decreased interaction with
FT FAS.
FT MUTAGEN 176 176 L->E: Decreased interaction with FAS.
FT CONFLICT 32 32 G -> V (in Ref. 2; CAA59197).
FT HELIX 3 13
FT HELIX 16 30
FT HELIX 34 38
FT STRAND 40 42
FT HELIX 43 51
FT HELIX 61 70
FT HELIX 74 82
FT STRAND 88 91
FT HELIX 94 105
FT STRAND 109 111
FT HELIX 112 118
FT HELIX 123 132
FT STRAND 133 135
FT HELIX 137 151
FT TURN 153 155
FT HELIX 158 167
FT HELIX 171 190
SQ SEQUENCE 208 AA; 23279 MW; 0E65E2F852E83507 CRC64;
MDPFLVLLHS VSSSLSSSEL TELKFLCLGR VGKRKLERVQ SGLDLFSMLL EQNDLEPGHT
ELLRELLASL RRHDLLRRVD DFEAGAAAGA APGEEDLCAA FNVICDNVGK DWRRLARQLK
VSDTKIDSIE DRYPRNLTER VRESLRIWKN TEKENATVAH LVGALRSCQM NLVADLVQEV
QQARDLQNRS GAMSPMSWNS DASTSEAS
//
ID FADD_HUMAN Reviewed; 208 AA.
AC Q13158; Q14866; Q6IBR4;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1997, sequence version 1.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=Protein FADD;
DE AltName: Full=FAS-associated death domain protein;
DE AltName: Full=FAS-associating death domain-containing protein;
DE AltName: Full=Growth-inhibiting gene 3 protein;
DE AltName: Full=Mediator of receptor induced toxicity;
GN Name=FADD; Synonyms=MORT1; ORFNames=GIG3;
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], AND MUTAGENESIS.
RC TISSUE=Umbilical vein endothelial cell;
RX PubMed=7538907; DOI=10.1016/0092-8674(95)90071-3;
RA Chinnaiyan A.M., O'Rourke K., Tewari M., Dixit V.M.;
RT "FADD, a novel death domain-containing protein, interacts with the
RT death domain of Fas and initiates apoptosis.";
RL Cell 81:505-512(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7536190; DOI=10.1074/jbc.270.14.7795;
RA Boldin M.P., Varfolomeev E.E., Pancer Z., Mett I.L., Camonis J.H.,
RA Wallach D.;
RT "A novel protein that interacts with the death domain of Fas/APO1
RT contains a sequence motif related to the death domain.";
RL J. Biol. Chem. 270:7795-7798(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kim J.W.;
RT "Identification of a human growth inhibition gene 3 (GIG3).";
RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (MAR-2006) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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 [10]
RP INTERACTION WITH PEA15.
RX PubMed=10442631; DOI=10.1038/sj.onc.1202831;
RA Condorelli G., Vigliotta G., Cafieri A., Trencia A., Andalo P.,
RA Oriente F., Miele C., Caruso M., Formisano P., Beguinot F.;
RT "PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-
RT induced apoptosis.";
RL Oncogene 18:4409-4415(1999).
RN [11]
RP INTERACTION WITH LRDD.
RX PubMed=10825539; DOI=10.1016/S0167-4838(00)00029-7;
RA Telliez J.-B., Bean K.M., Lin L.-L.;
RT "LRDD, a novel leucine rich repeat and death domain containing
RT protein.";
RL Biochim. Biophys. Acta 1478:280-288(2000).
RN [12]
RP IDENTIFICATION IN A COMPLEX WITH HIPK3 AND FAS, AND PHOSPHORYLATION AT
RP SER-194.
RX PubMed=11034606; DOI=10.1084/jem.192.8.1165;
RA Rochat-Steiner V., Becker K., Micheau O., Schneider P., Burns K.,
RA Tschopp J.;
RT "FIST/HIPK3: a Fas/FADD-interacting serine/threonine kinase that
RT induces FADD phosphorylation and inhibits Fas-mediated Jun NH2-
RT terminal kinase activation.";
RL J. Exp. Med. 192:1165-1174(2000).
RN [13]
RP INTERACTION WITH MBD4.
RX PubMed=12702765; DOI=10.1073/pnas.0431215100;
RA Screaton R.A., Kiessling S., Sansom O.J., Millar C.B., Maddison K.,
RA Bird A., Clarke A.R., Frisch S.M.;
RT "Fas-associated death domain protein interacts with methyl-CpG binding
RT domain protein 4: a potential link between genome surveillance and
RT apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:5211-5216(2003).
RN [14]
RP INTERACTION WITH MAVS.
RX PubMed=16127453; DOI=10.1038/ni1243;
RA Kawai T., Takahashi K., Sato S., Coban C., Kumar H., Kato H.,
RA Ishii K.J., Takeuchi O., Akira S.;
RT "IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I
RT interferon induction.";
RL Nat. Immunol. 6:981-988(2005).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-194, AND MASS
RP SPECTROMETRY.
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 [17]
RP FUNCTION IN INTERFERON-MEDIATED IMMUNITY, INTERACTION WITH FAS,
RP VARIANT IEHDCM TRP-105, AND CHARACTERIZATION OF VARIANT IEHDCM
RP TRP-105.
RX PubMed=21109225; DOI=10.1016/j.ajhg.2010.10.028;
RA Bolze A., Byun M., McDonald D., Morgan N.V., Abhyankar A.,
RA Premkumar L., Puel A., Bacon C.M., Rieux-Laucat F., Pang K.,
RA Britland A., Abel L., Cant A., Maher E.R., Riedl S.J., Hambleton S.,
RA Casanova J.L.;
RT "Whole-exome-sequencing-based discovery of human FADD deficiency.";
RL Am. J. Hum. Genet. 87:873-881(2010).
RN [18]
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 [19]
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 [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-194, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [21]
RP STRUCTURE BY NMR OF 1-83.
RX PubMed=9582077; DOI=10.1038/31972;
RA Eberstadt M., Huang B., Chen Z., Meadows R.P., Ng S.C., Zheng L.,
RA Lenardo M.J., Fesik S.W.;
RT "NMR structure and mutagenesis of the FADD (Mort1) death-effector
RT domain.";
RL Nature 392:941-945(1998).
RN [22]
RP STRUCTURE BY NMR OF 93-192.
RX PubMed=10964568; DOI=10.1006/jmbi.2000.4011;
RA Berglund H., Olerenshaw D., Sankar A., Federwisch M., McDonald N.Q.,
RA Driscoll P.C.;
RT "The three-dimensional solution structure and dynamic properties of
RT the human FADD death domain.";
RL J. Mol. Biol. 302:171-188(2000).
RN [23]
RP STRUCTURE BY NMR OF 2-191, FUNCTION, INTERACTION WITH FAS AND CASP8,
RP AND MUTAGENESIS OF SER-12; PHE-25; LYS-33; ARG-38; ASP-44 AND GLU-51.
RX PubMed=16762833; DOI=10.1016/j.molcel.2006.04.018;
RA Carrington P.E., Sandu C., Wei Y., Hill J.M., Morisawa G., Huang T.,
RA Gavathiotis E., Wei Y., Werner M.H.;
RT "The structure of FADD and its mode of interaction with procaspase-
RT 8.";
RL Mol. Cell 22:599-610(2006).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.73 ANGSTROMS) OF 93-208 IN COMPLEX WITH FAS,
RP FUNCTION, SUBUNIT, ELECTRON MICROSCOPY, DOMAIN, AND MUTAGENESIS OF
RP LEU-172 AND LEU-176.
RX PubMed=19118384; DOI=10.1038/nature07606;
RA Scott F.L., Stec B., Pop C., Dobaczewska M.K., Lee J.J., Monosov E.,
RA Robinson H., Salvesen G.S., Schwarzenbacher R., Riedl S.J.;
RT "The Fas-FADD death domain complex structure unravels signalling by
RT receptor clustering.";
RL Nature 457:1019-1022(2009).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (6.80 ANGSTROMS) OF 93-184 IN COMPLEX WITH FAS,
RP ELECTRON MICROSCOPY, FUNCTION, MASS SPECTROMETRY, SUBUNIT, AND
RP MUTAGENESIS OF ARG-117; ASP-123; ARG-135; ARG-142; LEU-172 AND
RP ASP-175.
RX PubMed=20935634; DOI=10.1038/nsmb.1920;
RA Wang L., Yang J.K., Kabaleeswaran V., Rice A.J., Cruz A.C., Park A.Y.,
RA Yin Q., Damko E., Jang S.B., Raunser S., Robinson C.V., Siegel R.M.,
RA Walz T., Wu H.;
RT "The Fas-FADD death domain complex structure reveals the basis of DISC
RT assembly and disease mutations.";
RL Nat. Struct. Mol. Biol. 17:1324-1329(2010).
CC -!- FUNCTION: Apoptotic adaptor molecule that recruits caspase-8 or
CC caspase-10 to the activated Fas (CD95) or TNFR-1 receptors. The
CC resulting aggregate called the death-inducing signaling complex
CC (DISC) performs caspase-8 proteolytic activation. Active caspase-8
CC initiates the subsequent cascade of caspases mediating apoptosis.
CC Involved in interferon-mediated antiviral immune response, playing
CC a role in the positive regulation of interferon signaling.
CC -!- SUBUNIT: Can self-associate. Interacts with CFLAR, PEA15 and MBD4.
CC When phosphorylated, part of a complex containing HIPK3 and FAS.
CC May interact with MAVS/IPS1. Interacts with MOCV v-CFLAR protein
CC and LRDD. Interacts (via death domain) with FAS (via death
CC domain). Interacts with CASP8.
CC -!- INTERACTION:
CC Self; NbExp=3; IntAct=EBI-494804, EBI-494804;
CC Q14790:CASP8; NbExp=32; IntAct=EBI-494804, EBI-78060;
CC Q14790-1:CASP8; NbExp=5; IntAct=EBI-494804, EBI-288309;
CC Q14790-5:CASP8; NbExp=4; IntAct=EBI-494804, EBI-288326;
CC P25445:FAS; NbExp=32; IntAct=EBI-494804, EBI-494743;
CC P25446:Fas (xeno); NbExp=5; IntAct=EBI-494804, EBI-296206;
CC P48023:FASLG; NbExp=2; IntAct=EBI-494804, EBI-495538;
CC Q5S007:LRRK2; NbExp=4; IntAct=EBI-494804, EBI-5323863;
CC O95243:MBD4; NbExp=6; IntAct=EBI-494804, EBI-348011;
CC Q99836:MYD88; NbExp=3; IntAct=EBI-494804, EBI-447677;
CC Q99497:PARK7; NbExp=9; IntAct=EBI-494804, EBI-1164361;
CC P53350:PLK1; NbExp=9; IntAct=EBI-494804, EBI-476768;
CC Q13546:RIPK1; NbExp=5; IntAct=EBI-494804, EBI-358507;
CC -!- TISSUE SPECIFICITY: Expressed in a wide variety of tissues, except
CC for peripheral blood mononuclear leukocytes.
CC -!- DOMAIN: Contains a death domain involved in the binding of the
CC corresponding domain within Fas receptor.
CC -!- DOMAIN: The interaction between the FAS and FADD death domains is
CC crucial for the formation of the death-inducing signaling complex
CC (DISC).
CC -!- DISEASE: Infections, recurrent, associated with encephalopathy,
CC hepatic dysfunction and cardiovascular malformations (IEHDCM)
CC [MIM:613759]: A condition with biological features of autoimmune
CC lymphoproliferative syndrome such as high-circulating
CC CD4(-)CD8(-)TCR-alpha-beta(+) T-cell counts, and elevated IL10 and
CC FASL levels. Affected individuals suffer from recurrent,
CC stereotypical episodes of fever, encephalopathy, and mild liver
CC dysfunction sometimes accompanied by generalized seizures. The
CC episodes can be triggered by varicella zoster virus (VZV), measles
CC mumps rubella (MMR) attenuated vaccine, parainfluenza virus, and
CC Epstein-Barr virus (EBV). Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 death domain.
CC -!- SIMILARITY: Contains 1 DED (death effector) domain.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/fadd/";
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DR EMBL; U24231; AAA86517.1; -; mRNA.
DR EMBL; X84709; CAA59197.1; -; mRNA.
DR EMBL; AY423721; AAS00484.1; -; mRNA.
DR EMBL; AK291005; BAF83694.1; -; mRNA.
DR EMBL; BT006927; AAP35573.1; -; mRNA.
DR EMBL; CR456738; CAG33019.1; -; mRNA.
DR EMBL; DQ449938; ABD96828.1; -; Genomic_DNA.
DR EMBL; CH471076; EAW74761.1; -; Genomic_DNA.
DR EMBL; BC000334; AAH00334.1; -; mRNA.
DR PIR; A56912; A56912.
DR RefSeq; NP_003815.1; NM_003824.3.
DR UniGene; Hs.86131; -.
DR PDB; 1A1W; NMR; -; A=1-83.
DR PDB; 1A1Z; NMR; -; A=1-83.
DR PDB; 1E3Y; NMR; -; A=93-192.
DR PDB; 1E41; NMR; -; A=93-192.
DR PDB; 2GF5; NMR; -; A=2-191.
DR PDB; 3EZQ; X-ray; 2.73 A; B/D/F/H/J/L/N/P=93-208.
DR PDB; 3OQ9; X-ray; 6.80 A; H/I/J/K/L=93-184.
DR PDBsum; 1A1W; -.
DR PDBsum; 1A1Z; -.
DR PDBsum; 1E3Y; -.
DR PDBsum; 1E41; -.
DR PDBsum; 2GF5; -.
DR PDBsum; 3EZQ; -.
DR PDBsum; 3OQ9; -.
DR ProteinModelPortal; Q13158; -.
DR SMR; Q13158; 2-191.
DR DIP; DIP-286N; -.
DR IntAct; Q13158; 27.
DR MINT; MINT-91814; -.
DR STRING; 9606.ENSP00000301838; -.
DR PhosphoSite; Q13158; -.
DR DMDM; 2498355; -.
DR PaxDb; Q13158; -.
DR PeptideAtlas; Q13158; -.
DR PRIDE; Q13158; -.
DR DNASU; 8772; -.
DR Ensembl; ENST00000301838; ENSP00000301838; ENSG00000168040.
DR GeneID; 8772; -.
DR KEGG; hsa:8772; -.
DR UCSC; uc001opm.2; human.
DR CTD; 8772; -.
DR GeneCards; GC11P070049; -.
DR HGNC; HGNC:3573; FADD.
DR HPA; CAB010209; -.
DR HPA; HPA001464; -.
DR MIM; 602457; gene.
DR MIM; 613759; phenotype.
DR neXtProt; NX_Q13158; -.
DR Orphanet; 306550; FADD-related immunodeficiency.
DR Orphanet; 99806; Oculootodental syndrome.
DR PharmGKB; PA27972; -.
DR eggNOG; NOG43830; -.
DR HOGENOM; HOG000112490; -.
DR HOVERGEN; HBG000853; -.
DR InParanoid; Q13158; -.
DR KO; K02373; -.
DR OMA; CQMNLVA; -.
DR OrthoDB; EOG76X61Z; -.
DR PhylomeDB; Q13158; -.
DR Reactome; REACT_578; Apoptosis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q13158; -.
DR EvolutionaryTrace; Q13158; -.
DR GeneWiki; FADD; -.
DR GenomeRNAi; 8772; -.
DR NextBio; 32890; -.
DR PRO; PR:Q13158; -.
DR ArrayExpress; Q13158; -.
DR Bgee; Q13158; -.
DR CleanEx; HS_FADD; -.
DR Genevestigator; Q13158; -.
DR GO; GO:0031265; C:CD95 death-inducing signaling complex; IDA:UniProtKB.
DR GO; GO:0044297; C:cell body; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR GO; GO:0097342; C:ripoptosome; IDA:UniProtKB.
DR GO; GO:0005123; F:death receptor binding; TAS:ProtInc.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:Reactome.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; IMP:UniProtKB.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; TAS:ProtInc.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0048535; P:lymph node development; ISS:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0070265; P:necrotic cell death; IMP:BHF-UCL.
DR GO; GO:0070236; P:negative regulation of activation-induced cell death of T cells; ISS:UniProtKB.
DR GO; GO:0042104; P:positive regulation of activated T cell proliferation; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:2000454; P:positive regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation; ISS:UniProtKB.
DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEP:UniProtKB.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; ISS:UniProtKB.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:BHF-UCL.
DR GO; GO:0045862; P:positive regulation of proteolysis; IDA:BHF-UCL.
DR GO; GO:0001916; P:positive regulation of T cell mediated cytotoxicity; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IDA:BHF-UCL.
DR GO; GO:0060340; P:positive regulation of type I interferon-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:2001239; P:regulation of extrinsic apoptotic signaling pathway in absence of ligand; TAS:Reactome.
DR GO; GO:0048536; P:spleen development; ISS:UniProtKB.
DR GO; GO:0033077; P:T cell differentiation in thymus; ISS:UniProtKB.
DR GO; GO:0043029; P:T cell homeostasis; ISS:UniProtKB.
DR GO; GO:0048538; P:thymus development; ISS:UniProtKB.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.533.10; -; 2.
DR InterPro; IPR011029; DEATH-like_dom.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR001875; DED.
DR InterPro; IPR016729; FADD.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF01335; DED; 1.
DR PIRSF; PIRSF018586; FADD; 1.
DR SMART; SM00005; DEATH; 1.
DR SMART; SM00031; DED; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR PROSITE; PS50017; DEATH_DOMAIN; 1.
DR PROSITE; PS50168; DED; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Apoptosis; Complete proteome; Disease mutation;
KW Host-virus interaction; Immunity; Innate immunity; Phosphoprotein;
KW Reference proteome.
FT CHAIN 1 208 Protein FADD.
FT /FTId=PRO_0000191279.
FT DOMAIN 3 81 DED.
FT DOMAIN 97 181 Death.
FT MOD_RES 194 194 Phosphoserine.
FT VARIANT 105 105 C -> W (in IEHDCM; reduced folding
FT stability as measured by differential
FT scanning calorimetry of the mutant
FT protein; impairs interaction with FAS).
FT /FTId=VAR_065124.
FT MUTAGEN 12 12 S->R: Loss of interaction with CASP8.
FT MUTAGEN 25 25 F->R: Loss of interaction with FAS. Loss
FT of self-association. Abolishes induction
FT of apoptosis.
FT MUTAGEN 33 33 K->E: Loss of self-association.
FT MUTAGEN 38 38 R->A: Loss of interaction with CASP8.
FT MUTAGEN 44 44 D->R: Loss of interaction with CASP8.
FT Abolishes induction of apoptosis.
FT Decreased interaction with FAS.
FT MUTAGEN 51 51 E->R: Loss of interaction with CASP8.
FT MUTAGEN 117 117 R->E: Loss of interaction with FAS.
FT MUTAGEN 121 121 V->N: Loss of interaction with FAS.
FT MUTAGEN 123 123 D->R: Strongly decreased interaction with
FT FAS.
FT MUTAGEN 135 135 R->E: Strongly decreased interaction with
FT FAS.
FT MUTAGEN 142 142 R->E: Decreased interaction with FAS.
FT MUTAGEN 172 172 L->A,E: Loss of interaction with FAS.
FT MUTAGEN 172 172 L->K: Strongly decreased interaction with
FT FAS.
FT MUTAGEN 175 175 D->K: Strongly decreased interaction with
FT FAS.
FT MUTAGEN 176 176 L->E: Decreased interaction with FAS.
FT CONFLICT 32 32 G -> V (in Ref. 2; CAA59197).
FT HELIX 3 13
FT HELIX 16 30
FT HELIX 34 38
FT STRAND 40 42
FT HELIX 43 51
FT HELIX 61 70
FT HELIX 74 82
FT STRAND 88 91
FT HELIX 94 105
FT STRAND 109 111
FT HELIX 112 118
FT HELIX 123 132
FT STRAND 133 135
FT HELIX 137 151
FT TURN 153 155
FT HELIX 158 167
FT HELIX 171 190
SQ SEQUENCE 208 AA; 23279 MW; 0E65E2F852E83507 CRC64;
MDPFLVLLHS VSSSLSSSEL TELKFLCLGR VGKRKLERVQ SGLDLFSMLL EQNDLEPGHT
ELLRELLASL RRHDLLRRVD DFEAGAAAGA APGEEDLCAA FNVICDNVGK DWRRLARQLK
VSDTKIDSIE DRYPRNLTER VRESLRIWKN TEKENATVAH LVGALRSCQM NLVADLVQEV
QQARDLQNRS GAMSPMSWNS DASTSEAS
//
MIM
602457
*RECORD*
*FIELD* NO
602457
*FIELD* TI
*602457 FAS-ASSOCIATED VIA DEATH DOMAIN; FADD
;;FAS-ASSOCIATING PROTEIN WITH DEATH DOMAIN;;
read moreMORT1
*FIELD* TX
DESCRIPTION
FADD is a universal adaptor protein in apoptosis that mediates signaling
of all known death domain-containing members of the TNF receptor
superfamily (Kabra et al., 2001).
CLONING
Two cell surface cytokine receptors, FAS (134637) and the tumor necrosis
factor (TNF) receptor (see TNFR1, 191190), trigger apoptosis by natural
ligands or specific agonist antibodies. Both receptors contain a
conserved intracellular death domain. Using a yeast 2-hybrid screen with
the cytoplasmic domain of FAS as bait, Chinnaiyan et al. (1995) isolated
FADD (FAS-associating protein with death domain) cDNAs. The predicted
208-amino acid protein contained a death domain that was 25 to 30%
identical to those of FAS and TNFR1. FADD interacted with FAS both in
vitro and in vivo.
GENE STRUCTURE
Kim et al. (1996) reported that the FADD gene contains 2 exons and spans
approximately 3.6 kb.
MAPPING
By analysis of somatic cell hybrid panels and by fluorescence in situ
hybridization, Kim et al. (1996) mapped the FADD gene to 11q13.3. They
noted that this region is amplified in several human malignancies (see
EMS1; 164765), and found that FADD, along with other genes on 11q13.3,
was amplified in a breast cancer cell line.
BIOCHEMICAL FEATURES
- Crystal Structure
Scott et al. (2009) successfully formed and isolated the human FAS
(134637)-FADD death domain complex and reported the 2.7-angstrom crystal
structure. The complex shows a tetrameric arrangement of 4 FADD death
domains bound to 4 FAS death domains. Scott et al. (2009) showed that an
opening of the FAS death domain exposes the FADD binding site and
simultaneously generates a FAS-FAS bridge. The result is a regulatory
FAS-FADD complex bridge governed by weak protein-protein interactions
revealing a model where the complex itself functions as a mechanistic
switch. This switch prevents accidental death-induced signaling complex
(DISC) assembly, yet allows for highly processive DISC formation and
clustering upon a sufficient stimulus. Scott et al. (2009) concluded
that, in addition to depicting a previously unknown mode of death domain
interactions, their results further uncover a mechanism for receptor
signaling solely by oligomerization and clustering events.
GENE FUNCTION
Chinnaiyan et al. (1995) demonstrated that the in vivo interaction of
FADD with FAS was due to the association of the respective death
domains. Overexpression of FADD in mammalian cells induced apoptosis,
which like FAS-induced apoptosis, was blocked by CrmA, a poxvirus gene
product. Northern blot analysis revealed that FADD is expressed as a
1.6-kb mRNA in many fetal and adult tissues. The authors concluded that
FADD may play an important role in the proximal signal transduction of
FAS. Yeh et al. (1998) stated that the interaction of FADD and FAS
through their C-terminal death domains unmasks the N-terminal effector
domain of FADD, allowing it to recruit caspase-8 (CASP8; 601763) to the
FAS signaling complex and thereby activating a cysteine protease
cascade, leading to cell death.
Balachandran et al. (2004) reported that mammalian cells lacking the
death domain-containing protein FADD are defective in intracellular
double-stranded RNA (dsRNA)-activated gene expression, including
production of type I (alpha/beta) interferons (e.g., 147660), and are
thus very susceptible to viral infection. The signaling pathway
incorporating FADD is largely independent of Toll-like receptor-3
(603029) and the dsRNA-dependent kinase PKR (176871) but seems to
require receptor-interacting protein-1 (RIPK1; 603453) as well as
TANK-binding kinase-1 (604834)-mediated activation of the transcription
factor IRF3 (603734). The requirement for FADD in mammalian host defense
is evocative of innate immune signaling in Drosophila, in which a
FADD-dependent pathway responds to bacterial infection by activating the
transcription of antimicrobial genes. Balachandran et al. (2004)
concluded that their data further suggest the existence of a conserved
pathogen recognition pathway in mammalian cells that is essential for
the optimal induction of type I interferons and other major genes
important for host defense.
Lee et al. (2007) showed that intrinsic apoptosis in human cells that
was induced by the chemotherapeutic agent etoposide or the antibiotic
staurosporine, but not by FAS ligand (TNFSF6; 134638) or TRAIL (TNFSF10;
603598), caused translocation of AK2 (103020) from mitochondria to the
cytoplasm, followed by formation of a complex between AK2, FADD, and
CASP10 (601762). Yeast 2-hybrid analysis, protein pull-down assays, and
immunoprecipitation analysis showed that the N- and C-terminal domains
of AK2, which include nucleoside- and substrate-binding domains,
respectively, bound the C-terminal death domain of FADD. AK2 binding
promoted association of CASP10 with FADD, and addition of purified AK2
protein to cell extracts induced activation of CASP10 via FADD, leading
to subsequent activation of CASP9 (602234) and CASP3 (600636). Apoptosis
through the AK2 complex did not correlate with the adenylate kinase
activity of AK2, did not require CASP8-mediated apoptotic responses, and
did not involve mitochondrial cytochrome c release. Immunodepletion or
knockdown of AK2, FADD, or CASP10 abrogated etoposide-induced apoptosis,
and AK2 complexes were not observed in several etoposide-resistant human
tumor cell lines that were deficient in expression of FADD, CASP10, or
CASP3. In contrast to the findings in human cells, etoposide-induced
apoptosis was observed in mouse embryonic fibroblasts that lacked Fadd
expression. Since mice also lack Casp10, Lee et al. (2007) concluded
that mice lack an apoptotic pathway comparable to the AK2-FADD-CASP10
pathway in humans.
Li et al. (2013) discovered that death domains in several proteins,
including TRADD (603500), FADD, RIPK1, and TNFR1 (191190), were directly
inactivated by NleB, an enteropathogenic E. coli type III secretion
system effector known to inhibit host NF-kappa-B (see 164011) signaling.
NleB contained an unprecedented N-acetylglucosamine (GlcNAc) transferase
activity that specifically modified a conserved arginine in these death
domains (arg235 in the TRADD death domain). NleB GlcNAcylation of death
domains blocked homotypic/heterotypic death domain interactions and
assembly of the oligomeric TNFR1 complex, thereby disrupting TNF
signaling in enteropathogenic E. coli infected cells, including
NF-kappa-B signaling, apoptosis, and necroptosis. Type III-delivered
NleB also blocked FAS ligand and TRAIL-induced cell death by preventing
formation of a FADD-mediated death-inducing signaling complex (DISC).
The arginine GlcNAc transferase activity of NleB was required for
bacterial colonization in the mouse model of enteropathogenic E. coli
infection.
Pearson et al. (2013) reported that the type III secretion system (T3SS)
effector NleB1 from enteropathogenic E. coli binds to host cell
death-domain-containing proteins and thereby inhibits death receptor
signaling. Protein interaction studies identified FADD, TRADD, and RIPK1
as binding partners of NleB1. NleB1 expressed ectopically or injected by
the bacterial T3SS prevented Fas ligand or TNF-induced formation of the
canonical DISC and proteolytic activation of caspase-8 (601763), an
essential step in death receptor-induced apoptosis. This inhibition
depended on the N-acetylglucosamine transferase activity of NleB1, which
specifically modified arg117 in the death domain of FADD. The importance
of the death receptor apoptotic pathway to host defense was demonstrated
using mice deficient in the FAS signaling pathway, which showed delayed
clearance of the enteropathogenic E. coli-like mouse pathogen
Citrobacter rodentium and reversion to virulence of an NleB mutant.
Pearson et al. (2013) concluded that the activity of NleB suggested that
enteropathogenic E. coli and other attaching and effacing pathogens
antagonize death receptor-induced apoptosis of infected cells, thereby
blocking a major antimicrobial host response.
MOLECULAR GENETICS
In 2 families with otodental dysplasia (166750) and 1 with otodental
dysplasia and coloboma, Gregory-Evans et al. (2007) identified
overlapping hemizygous microdeletions on chromosome 11q13, the smallest
of which spanned 43 kb and involved the FGF3 gene (164950). In the
family with otodental dysplasia and coloboma, the microdeletion was
spanned 490 kb and encompassed the FADD gene. Spatiotemporal in situ
hybridization in zebrafish embryos showed that FADD is expressed during
eye development. Gregory-Evans et al. (2007) suggested that FGF3
haploinsufficiency is likely the cause of otodental syndrome and that
FADD haploinsufficiency accounts for the associated ocular coloboma.
In 2 sisters and their cousin from a large consanguineous Pakistani
pedigree, who had recurrent infections associated with encephalopathy,
hepatic dysfunction, and cardiovascular malformations (613759), Bolze et
al. (2010) identified homozygosity for a missense mutation in the FADD
gene (602457.0001).
ANIMAL MODEL
Yeh et al. (1998) found that FAS (CD95), TNFR1, and death receptor 3
(603366) did not induce apoptosis in FADD-deficient embryonic
fibroblasts, whereas DR4, oncogenes E1A and c-myc (190080), and
chemotherapeutic agent adriamycin did. Mice with a deletion in the FADD
gene did not survive beyond day 11.5 of embryogenesis; these mice showed
signs of cardiac failure and abdominal hemorrhage. Chimeric embryos
showing a high contribution of FADD-null mutant cells to the heart
reproduced the phenotype of FADD-deficient mutants. Thus, not only death
receptors but also receptors that couple to developmental programs may
use FADD for signaling. Since FAS is necessary for homeostasis in the
immune system, Zhang et al. (1998) investigated the effect of FADD
deletion in lymphoid organs. Since FADD-null mice die in utero, they
used FADD-null, RAG1 (179615)-null chimeras in which all mature
lymphocytes were derived from the FADD-null cells, as RAG1-null mice are
not capable of producing B or T cells. FAS-induced apoptosis was
completely blocked in thymocytes from the FADD-null mice, indicating
that there are no redundant FAS apoptotic pathways. Although thymocyte
subpopulations were apparently normal in newborn chimeras, the
thymocytes decreased to undetectable levels as these mice age.
Peripheral T cells were present in all older FADD-null chimeras, but
activation-induced proliferation was impaired despite production of IL2
(147680). These results and the similarities between FADD-null mice and
mice lacking the beta-subunits of the IL2 receptor (IL2RB; 146710),
suggested to Zhang et al. (1998) that there is an unexpected connection
between cell proliferation and apoptosis.
FADD-null mutations in mice are embryonic-lethal, and analysis of FADD
-/- T cells from RAG-1 -/- reconstituted chimeras suggested a role for
FADD in proliferation of mature T cells. Kabra et al. (2001) reported
the generation of T cell-specific FADD-deficient mice via a conditional
genomic rescue approach. They found that FADD deficiency led to
inhibition of T cell development at the CD4(-)/CD8(-) stage and a
reduction in the number of mature T cells. The FADD mutation did not
affect apoptosis or the proximal signaling events of the pre-T-cell
receptor; introduction of a T-cell receptor transgene failed to rescue
the mutant phenotype. These data suggested that FADD, through either a
death domain-containing receptor or a novel receptor-independent
mechanism, is required for the proliferative phase of early T cell
development.
Zhang et al. (2011) showed that FADD-null embryos contain raised levels
of RIP1 (1603453) and exhibit massive necrosis. To investigate a
potential in vivo functional interaction between RIP1 and FADD, null
alleles of RIP1 were crossed into Fadd-null mice. Notably, RIP1
deficiency allowed normal embryogenesis of Fadd-null mice. Conversely,
the developmental defect of Rip1-null lymphocytes was partially
corrected by FADD deletion. Furthermore, RIP1 deficiency fully restored
normal proliferation in Fadd-null T cells but not in Fadd-null B cells.
Fadd-null/Rip1-null double-knockout T cells are resistant to death
induced by Fas or TNF-alpha (191160) and show reduced NF-kappa-B (see
164011) activity. Therefore, Zhang et al. (2011) concluded that their
data demonstrated an unexpected cell type-specific interplay between
FADD and RIP1, which is critical for the regulation of apoptosis and
necrosis during embryogenesis and lymphocyte function.
Welz et al. (2011) showed that mice with intestinal epithelial cell
(IEC)-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein
required for death receptor-induced apoptosis, spontaneously developed
epithelial cell necrosis, loss of Paneth cells, enteritis, and severe
erosive colitis. Genetic deficiency in RIP3 (605817), a critical
regulator of programmed necrosis, prevented the development of
spontaneous pathology in both the small intestine and colon of
FADD(IEC-KO) mice, demonstrating that intestinal inflammation is
triggered by RIP3-dependent death of FADD-deficient IECs.
Epithelial-specific inhibition of CYLD (605018), a deubiquitinase that
regulates cellular necrosis, prevented colitis development in
FADD(IEC-KO) but not in NEMO(IEC-KO) (300248) mice, showing that
different mechanisms mediated death of colonic epithelial cells in these
2 models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon
inflammation, whereas MYD88 (602170) deficiency and also elimination of
the microbiota prevented colon inflammation, indicating that
bacteria-mediated Toll-like receptor signaling drives colitis by
inducing the expression of TNF and other cytokines. However, neither
CYLD, TNF, or MYD88 deficiency nor elimination of the microbiota could
prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing
that different mechanisms drive RIP3-dependent necrosis of
FADD-deficient IECs in the small and large bowel. Therefore, by
inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier
integrity and antibacterial defense, maintains homeostasis, and prevents
chronic intestinal inflammation. Welz et al. (2011) concluded that,
collectively, their results showed that mechanisms preventing
RIP3-mediated epithelial cell death are critical for the maintenance of
intestinal homeostasis and indicated that programmed necrosis of IECs
might be implicated in the pathogenesis of inflammatory bowel disease,
in which Paneth cell and barrier defects are thought to contribute to
intestinal inflammation.
*FIELD* AV
.0001
INFECTIONS, RECURRENT, ASSOCIATED WITH ENCEPHALOPATHY, HEPATIC DYSFUNCTION,
AND CARDIOVASCULAR MALFORMATIONS
FADD, CYS105TRP
In 2 sisters and their cousin from a large consanguineous Pakistani
pedigree with recurrent infections associated with encephalopathy,
hepatic dysfunction, and cardiovascular malformations (613759), Bolze et
al. (2010) identified homozygosity for a 315T-G transversion in exon 2
of the FADD gene, resulting in a cys105-to-trp (C105W) substitution at a
highly conserved residue in alpha-helix-1 of the FADD death domain (DD),
at the interface of the FAS (134637)-FADD complex. The mutation
segregated with disease in the family and was not found in 282 Pakistani
controls. Analysis of patient EBV-B cells showed levels of FADD mRNA
that were similar to controls; however, FADD protein levels were clearly
lower in patient fibroblasts (16% and 21%) and a heterozygous relative
(62%) compared to controls. Differential scanning calorimetry showed
that the folding stability of the mutant protein was lower than that of
wildtype by 10 degrees C, and gel copurification assay showed that
binding levels for C105W-mutant FADD with FAS were lower than those for
wildtype FADD, suggesting that the primary FAS-FADD complex was less
stable. Bolze et al. (2010) concluded that the C105W mutation strongly
decreases steady-state protein levels and impairs the interaction of the
residual FADD protein with FAS. Analysis of FAS-induced apoptosis in
patients' cells confirmed that the C105W mutant impairs apoptotic
function both in vitro and in vivo.
*FIELD* RF
1. Balachandran, S.; Thomas, E.; Barber, G. N.: A FADD-dependent
innate immune mechanism in mammalian cells. Nature 432: 401-405,
2004.
2. Bolze, A.; Byun, M.; McDonald, D.; Morgan, N. V.; Abhyankar, A.;
Premkumar, L.; Puel, A.; Bacon, C. M.; Rieux-Laucat, F.; Pang, K.;
Britland, A.; Abel, L.; Cant, A.; Maher, E. R.; Riedl, S. J.; Hambleton,
S.; Casanova, J.-L.: Whole-exome-sequencing-based discovery of human
FADD deficiency. Am. J. Hum. Genet. 87: 873-881, 2010.
3. Chinnaiyan, A. M.; O'Rourke, K.; Tewari, M.; Dixit, V. M.: FADD,
a novel death domain-containing protein, interacts with the death
domain of Fas and initiates apoptosis. Cell 81: 505-512, 1995.
4. Gregory-Evans, C. Y.; Moosajee, M.; Hodges, M. D.; Mackay, D. S.;
Game, L.; Vargesson, N.; Bloch-Zupan, A.; Ruschendorf, F.; Santos-Pinto,
L.; Wackens, G.; Gregory-Evans, K.: SNP genome scanning localizes
oto-dental syndrome to chromosome 11q13 and microdeletions at this
locus implicate FGF3 in dental and inner-ear disease and FADD in ocular
coloboma. Hum. Molec. Genet. 16: 2482-2493, 2007.
5. Kabra, N. H.; Kang, C.; Hsing, L. C.; Zhang, J.; Winoto, A.: T
cell-specific FADD-deficient mice: FADD is required for early T cell
development. Proc. Nat. Acad. Sci. 98: 6307-6312, 2001.
6. Kim, P. K. M.; Dutra, A. S.; Chandrasekharappa, S. C.; Puck, J.
M.: Genomic structure and mapping of human FADD, an intracellular
mediator of lymphocyte apoptosis. J. Immun. 157: 5461-5466, 1996.
7. Lee, H.-J.; Pyo, J.-O.; Oh, Y.; Kim, H.-J.; Hong, S.; Jeon, Y.-J.;
Kim, H.; Cho, D.-H.; Woo, H.-N.; Song, S.; Nam, J.-H.; Kim, H. J.;
Kim, K.-S.; Jung, Y.-K.: AK2 activates a novel apoptotic pathway
through formation of a complex with FADD and caspase-10. Nature Cell
Biol. 9: 1303-1310, 2007.
8. Li, S.; Zhang, L.; Yao, Q.; Li, L.; Dong, N.; Rong, J.; Gao, W.;
Ding, X.; Sun, L.; Chen, X.; Chen, S.; Shao, F.: Pathogen blocks
host death receptor signaling by arginine GlcNAcylation of death domains. Nature 501:
242-246, 2013.
9. Pearson, J. S.; Giogha, C.; Ong, S. Y.; Kennedy, C. L.; Kelly,
M.; Robinson, K. S.; Lung, T. W. F.; Mansell, A.; Riedmaier, P.; Oates,
C. V. L.; Zaid, A.; Muhlen, S.; and 13 others: A type III effector
antagonizes death receptor signalling during bacterial gut infection. Nature 501:
247-251, 2013.
10. Scott, F. L.; Stec, B.; Pop, C.; Dobaczewska, M. K.; Lee, J. J.;
Monosov, E.; Robinson, H.; Salvesen, G. S.; Schwarzenbacher, R.; Riedl,
S. J.: The Fas-FADD death domain complex structure unravels signalling
by receptor clustering. Nature 457: 1019-1022, 2009.
11. Welz, P.-S.; Wullaert, A.; Vlantis, K.; Kondylis, V.; Fernandez-Majada,
V.; Ermolaeva, M.; Kirsch, P.; Sterner-Kock, A.; van Loo, G.; Pasparakis,
M.: FADD prevents RIP3-mediated epithelial cell necrosis and chronic
intestinal inflammation. Nature 477: 330-334, 2011.
12. Yeh, W.-C.; de la Pompa, J. L.; McCurrach, M. E.; Shu, H.-B.;
Elia, A. J.; Shahinian, A.; Ng, M.; Wakeham, A.; Khoo, W.; Mitchell,
K.; El-Deiry, W. S.; Lowe, S. W.; Goeddel, D. V.; Mak, T. W.: FADD:
essential for embryo development and signaling from some, but not
all, inducers of apoptosis. Science 279: 1954-1958, 1998.
13. Zhang, H.; Zhou, X.; McQuade, T.; Li, J.; Chan, F. K.-M.; Zhang,
J.: Functional complementation between FADD and RIP1 in embryos and
lymphocytes. Nature 471: 373-376, 2011. Note: Erratum: Nature 483:
498 only, 2012.
14. Zhang, J.; Cado, D.; Chen, A.; Kabra, N. H.; Winoto, A.: Fas-mediated
apoptosis and activation-induced T-cell proliferation are defective
in mice lacking FADD/Mort1. Nature 392: 296-300, 1998.
*FIELD* CN
Ada Hamosh - updated: 12/12/2013
Ada Hamosh - updated: 12/11/2013
Ada Hamosh - updated: 11/22/2011
Ada Hamosh - updated: 6/7/2011
Marla J. F. O'Neill - updated: 2/16/2011
Marla J. F. O'Neill - updated: 11/30/2009
Ada Hamosh - updated: 3/10/2009
Patricia A. Hartz - updated: 10/28/2008
Ada Hamosh - updated: 12/10/2004
Victor A. McKusick - updated: 6/27/2001
Rebekah S. Rasooly - updated: 1/13/1999
*FIELD* CD
Victor A. McKusick: 3/20/1998
*FIELD* ED
alopez: 12/12/2013
alopez: 12/11/2013
alopez: 4/25/2012
alopez: 11/30/2011
alopez: 11/29/2011
terry: 11/22/2011
alopez: 6/14/2011
terry: 6/7/2011
wwang: 2/22/2011
terry: 2/16/2011
wwang: 12/17/2009
terry: 11/30/2009
alopez: 3/12/2009
terry: 3/10/2009
mgross: 10/28/2008
wwang: 5/15/2007
alopez: 12/15/2004
terry: 12/10/2004
alopez: 10/30/2001
cwells: 7/11/2001
terry: 6/27/2001
alopez: 5/12/1999
alopez: 1/14/1999
alopez: 1/13/1999
alopez: 1/5/1999
alopez: 12/18/1998
alopez: 3/20/1998
*RECORD*
*FIELD* NO
602457
*FIELD* TI
*602457 FAS-ASSOCIATED VIA DEATH DOMAIN; FADD
;;FAS-ASSOCIATING PROTEIN WITH DEATH DOMAIN;;
read moreMORT1
*FIELD* TX
DESCRIPTION
FADD is a universal adaptor protein in apoptosis that mediates signaling
of all known death domain-containing members of the TNF receptor
superfamily (Kabra et al., 2001).
CLONING
Two cell surface cytokine receptors, FAS (134637) and the tumor necrosis
factor (TNF) receptor (see TNFR1, 191190), trigger apoptosis by natural
ligands or specific agonist antibodies. Both receptors contain a
conserved intracellular death domain. Using a yeast 2-hybrid screen with
the cytoplasmic domain of FAS as bait, Chinnaiyan et al. (1995) isolated
FADD (FAS-associating protein with death domain) cDNAs. The predicted
208-amino acid protein contained a death domain that was 25 to 30%
identical to those of FAS and TNFR1. FADD interacted with FAS both in
vitro and in vivo.
GENE STRUCTURE
Kim et al. (1996) reported that the FADD gene contains 2 exons and spans
approximately 3.6 kb.
MAPPING
By analysis of somatic cell hybrid panels and by fluorescence in situ
hybridization, Kim et al. (1996) mapped the FADD gene to 11q13.3. They
noted that this region is amplified in several human malignancies (see
EMS1; 164765), and found that FADD, along with other genes on 11q13.3,
was amplified in a breast cancer cell line.
BIOCHEMICAL FEATURES
- Crystal Structure
Scott et al. (2009) successfully formed and isolated the human FAS
(134637)-FADD death domain complex and reported the 2.7-angstrom crystal
structure. The complex shows a tetrameric arrangement of 4 FADD death
domains bound to 4 FAS death domains. Scott et al. (2009) showed that an
opening of the FAS death domain exposes the FADD binding site and
simultaneously generates a FAS-FAS bridge. The result is a regulatory
FAS-FADD complex bridge governed by weak protein-protein interactions
revealing a model where the complex itself functions as a mechanistic
switch. This switch prevents accidental death-induced signaling complex
(DISC) assembly, yet allows for highly processive DISC formation and
clustering upon a sufficient stimulus. Scott et al. (2009) concluded
that, in addition to depicting a previously unknown mode of death domain
interactions, their results further uncover a mechanism for receptor
signaling solely by oligomerization and clustering events.
GENE FUNCTION
Chinnaiyan et al. (1995) demonstrated that the in vivo interaction of
FADD with FAS was due to the association of the respective death
domains. Overexpression of FADD in mammalian cells induced apoptosis,
which like FAS-induced apoptosis, was blocked by CrmA, a poxvirus gene
product. Northern blot analysis revealed that FADD is expressed as a
1.6-kb mRNA in many fetal and adult tissues. The authors concluded that
FADD may play an important role in the proximal signal transduction of
FAS. Yeh et al. (1998) stated that the interaction of FADD and FAS
through their C-terminal death domains unmasks the N-terminal effector
domain of FADD, allowing it to recruit caspase-8 (CASP8; 601763) to the
FAS signaling complex and thereby activating a cysteine protease
cascade, leading to cell death.
Balachandran et al. (2004) reported that mammalian cells lacking the
death domain-containing protein FADD are defective in intracellular
double-stranded RNA (dsRNA)-activated gene expression, including
production of type I (alpha/beta) interferons (e.g., 147660), and are
thus very susceptible to viral infection. The signaling pathway
incorporating FADD is largely independent of Toll-like receptor-3
(603029) and the dsRNA-dependent kinase PKR (176871) but seems to
require receptor-interacting protein-1 (RIPK1; 603453) as well as
TANK-binding kinase-1 (604834)-mediated activation of the transcription
factor IRF3 (603734). The requirement for FADD in mammalian host defense
is evocative of innate immune signaling in Drosophila, in which a
FADD-dependent pathway responds to bacterial infection by activating the
transcription of antimicrobial genes. Balachandran et al. (2004)
concluded that their data further suggest the existence of a conserved
pathogen recognition pathway in mammalian cells that is essential for
the optimal induction of type I interferons and other major genes
important for host defense.
Lee et al. (2007) showed that intrinsic apoptosis in human cells that
was induced by the chemotherapeutic agent etoposide or the antibiotic
staurosporine, but not by FAS ligand (TNFSF6; 134638) or TRAIL (TNFSF10;
603598), caused translocation of AK2 (103020) from mitochondria to the
cytoplasm, followed by formation of a complex between AK2, FADD, and
CASP10 (601762). Yeast 2-hybrid analysis, protein pull-down assays, and
immunoprecipitation analysis showed that the N- and C-terminal domains
of AK2, which include nucleoside- and substrate-binding domains,
respectively, bound the C-terminal death domain of FADD. AK2 binding
promoted association of CASP10 with FADD, and addition of purified AK2
protein to cell extracts induced activation of CASP10 via FADD, leading
to subsequent activation of CASP9 (602234) and CASP3 (600636). Apoptosis
through the AK2 complex did not correlate with the adenylate kinase
activity of AK2, did not require CASP8-mediated apoptotic responses, and
did not involve mitochondrial cytochrome c release. Immunodepletion or
knockdown of AK2, FADD, or CASP10 abrogated etoposide-induced apoptosis,
and AK2 complexes were not observed in several etoposide-resistant human
tumor cell lines that were deficient in expression of FADD, CASP10, or
CASP3. In contrast to the findings in human cells, etoposide-induced
apoptosis was observed in mouse embryonic fibroblasts that lacked Fadd
expression. Since mice also lack Casp10, Lee et al. (2007) concluded
that mice lack an apoptotic pathway comparable to the AK2-FADD-CASP10
pathway in humans.
Li et al. (2013) discovered that death domains in several proteins,
including TRADD (603500), FADD, RIPK1, and TNFR1 (191190), were directly
inactivated by NleB, an enteropathogenic E. coli type III secretion
system effector known to inhibit host NF-kappa-B (see 164011) signaling.
NleB contained an unprecedented N-acetylglucosamine (GlcNAc) transferase
activity that specifically modified a conserved arginine in these death
domains (arg235 in the TRADD death domain). NleB GlcNAcylation of death
domains blocked homotypic/heterotypic death domain interactions and
assembly of the oligomeric TNFR1 complex, thereby disrupting TNF
signaling in enteropathogenic E. coli infected cells, including
NF-kappa-B signaling, apoptosis, and necroptosis. Type III-delivered
NleB also blocked FAS ligand and TRAIL-induced cell death by preventing
formation of a FADD-mediated death-inducing signaling complex (DISC).
The arginine GlcNAc transferase activity of NleB was required for
bacterial colonization in the mouse model of enteropathogenic E. coli
infection.
Pearson et al. (2013) reported that the type III secretion system (T3SS)
effector NleB1 from enteropathogenic E. coli binds to host cell
death-domain-containing proteins and thereby inhibits death receptor
signaling. Protein interaction studies identified FADD, TRADD, and RIPK1
as binding partners of NleB1. NleB1 expressed ectopically or injected by
the bacterial T3SS prevented Fas ligand or TNF-induced formation of the
canonical DISC and proteolytic activation of caspase-8 (601763), an
essential step in death receptor-induced apoptosis. This inhibition
depended on the N-acetylglucosamine transferase activity of NleB1, which
specifically modified arg117 in the death domain of FADD. The importance
of the death receptor apoptotic pathway to host defense was demonstrated
using mice deficient in the FAS signaling pathway, which showed delayed
clearance of the enteropathogenic E. coli-like mouse pathogen
Citrobacter rodentium and reversion to virulence of an NleB mutant.
Pearson et al. (2013) concluded that the activity of NleB suggested that
enteropathogenic E. coli and other attaching and effacing pathogens
antagonize death receptor-induced apoptosis of infected cells, thereby
blocking a major antimicrobial host response.
MOLECULAR GENETICS
In 2 families with otodental dysplasia (166750) and 1 with otodental
dysplasia and coloboma, Gregory-Evans et al. (2007) identified
overlapping hemizygous microdeletions on chromosome 11q13, the smallest
of which spanned 43 kb and involved the FGF3 gene (164950). In the
family with otodental dysplasia and coloboma, the microdeletion was
spanned 490 kb and encompassed the FADD gene. Spatiotemporal in situ
hybridization in zebrafish embryos showed that FADD is expressed during
eye development. Gregory-Evans et al. (2007) suggested that FGF3
haploinsufficiency is likely the cause of otodental syndrome and that
FADD haploinsufficiency accounts for the associated ocular coloboma.
In 2 sisters and their cousin from a large consanguineous Pakistani
pedigree, who had recurrent infections associated with encephalopathy,
hepatic dysfunction, and cardiovascular malformations (613759), Bolze et
al. (2010) identified homozygosity for a missense mutation in the FADD
gene (602457.0001).
ANIMAL MODEL
Yeh et al. (1998) found that FAS (CD95), TNFR1, and death receptor 3
(603366) did not induce apoptosis in FADD-deficient embryonic
fibroblasts, whereas DR4, oncogenes E1A and c-myc (190080), and
chemotherapeutic agent adriamycin did. Mice with a deletion in the FADD
gene did not survive beyond day 11.5 of embryogenesis; these mice showed
signs of cardiac failure and abdominal hemorrhage. Chimeric embryos
showing a high contribution of FADD-null mutant cells to the heart
reproduced the phenotype of FADD-deficient mutants. Thus, not only death
receptors but also receptors that couple to developmental programs may
use FADD for signaling. Since FAS is necessary for homeostasis in the
immune system, Zhang et al. (1998) investigated the effect of FADD
deletion in lymphoid organs. Since FADD-null mice die in utero, they
used FADD-null, RAG1 (179615)-null chimeras in which all mature
lymphocytes were derived from the FADD-null cells, as RAG1-null mice are
not capable of producing B or T cells. FAS-induced apoptosis was
completely blocked in thymocytes from the FADD-null mice, indicating
that there are no redundant FAS apoptotic pathways. Although thymocyte
subpopulations were apparently normal in newborn chimeras, the
thymocytes decreased to undetectable levels as these mice age.
Peripheral T cells were present in all older FADD-null chimeras, but
activation-induced proliferation was impaired despite production of IL2
(147680). These results and the similarities between FADD-null mice and
mice lacking the beta-subunits of the IL2 receptor (IL2RB; 146710),
suggested to Zhang et al. (1998) that there is an unexpected connection
between cell proliferation and apoptosis.
FADD-null mutations in mice are embryonic-lethal, and analysis of FADD
-/- T cells from RAG-1 -/- reconstituted chimeras suggested a role for
FADD in proliferation of mature T cells. Kabra et al. (2001) reported
the generation of T cell-specific FADD-deficient mice via a conditional
genomic rescue approach. They found that FADD deficiency led to
inhibition of T cell development at the CD4(-)/CD8(-) stage and a
reduction in the number of mature T cells. The FADD mutation did not
affect apoptosis or the proximal signaling events of the pre-T-cell
receptor; introduction of a T-cell receptor transgene failed to rescue
the mutant phenotype. These data suggested that FADD, through either a
death domain-containing receptor or a novel receptor-independent
mechanism, is required for the proliferative phase of early T cell
development.
Zhang et al. (2011) showed that FADD-null embryos contain raised levels
of RIP1 (1603453) and exhibit massive necrosis. To investigate a
potential in vivo functional interaction between RIP1 and FADD, null
alleles of RIP1 were crossed into Fadd-null mice. Notably, RIP1
deficiency allowed normal embryogenesis of Fadd-null mice. Conversely,
the developmental defect of Rip1-null lymphocytes was partially
corrected by FADD deletion. Furthermore, RIP1 deficiency fully restored
normal proliferation in Fadd-null T cells but not in Fadd-null B cells.
Fadd-null/Rip1-null double-knockout T cells are resistant to death
induced by Fas or TNF-alpha (191160) and show reduced NF-kappa-B (see
164011) activity. Therefore, Zhang et al. (2011) concluded that their
data demonstrated an unexpected cell type-specific interplay between
FADD and RIP1, which is critical for the regulation of apoptosis and
necrosis during embryogenesis and lymphocyte function.
Welz et al. (2011) showed that mice with intestinal epithelial cell
(IEC)-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein
required for death receptor-induced apoptosis, spontaneously developed
epithelial cell necrosis, loss of Paneth cells, enteritis, and severe
erosive colitis. Genetic deficiency in RIP3 (605817), a critical
regulator of programmed necrosis, prevented the development of
spontaneous pathology in both the small intestine and colon of
FADD(IEC-KO) mice, demonstrating that intestinal inflammation is
triggered by RIP3-dependent death of FADD-deficient IECs.
Epithelial-specific inhibition of CYLD (605018), a deubiquitinase that
regulates cellular necrosis, prevented colitis development in
FADD(IEC-KO) but not in NEMO(IEC-KO) (300248) mice, showing that
different mechanisms mediated death of colonic epithelial cells in these
2 models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon
inflammation, whereas MYD88 (602170) deficiency and also elimination of
the microbiota prevented colon inflammation, indicating that
bacteria-mediated Toll-like receptor signaling drives colitis by
inducing the expression of TNF and other cytokines. However, neither
CYLD, TNF, or MYD88 deficiency nor elimination of the microbiota could
prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing
that different mechanisms drive RIP3-dependent necrosis of
FADD-deficient IECs in the small and large bowel. Therefore, by
inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier
integrity and antibacterial defense, maintains homeostasis, and prevents
chronic intestinal inflammation. Welz et al. (2011) concluded that,
collectively, their results showed that mechanisms preventing
RIP3-mediated epithelial cell death are critical for the maintenance of
intestinal homeostasis and indicated that programmed necrosis of IECs
might be implicated in the pathogenesis of inflammatory bowel disease,
in which Paneth cell and barrier defects are thought to contribute to
intestinal inflammation.
*FIELD* AV
.0001
INFECTIONS, RECURRENT, ASSOCIATED WITH ENCEPHALOPATHY, HEPATIC DYSFUNCTION,
AND CARDIOVASCULAR MALFORMATIONS
FADD, CYS105TRP
In 2 sisters and their cousin from a large consanguineous Pakistani
pedigree with recurrent infections associated with encephalopathy,
hepatic dysfunction, and cardiovascular malformations (613759), Bolze et
al. (2010) identified homozygosity for a 315T-G transversion in exon 2
of the FADD gene, resulting in a cys105-to-trp (C105W) substitution at a
highly conserved residue in alpha-helix-1 of the FADD death domain (DD),
at the interface of the FAS (134637)-FADD complex. The mutation
segregated with disease in the family and was not found in 282 Pakistani
controls. Analysis of patient EBV-B cells showed levels of FADD mRNA
that were similar to controls; however, FADD protein levels were clearly
lower in patient fibroblasts (16% and 21%) and a heterozygous relative
(62%) compared to controls. Differential scanning calorimetry showed
that the folding stability of the mutant protein was lower than that of
wildtype by 10 degrees C, and gel copurification assay showed that
binding levels for C105W-mutant FADD with FAS were lower than those for
wildtype FADD, suggesting that the primary FAS-FADD complex was less
stable. Bolze et al. (2010) concluded that the C105W mutation strongly
decreases steady-state protein levels and impairs the interaction of the
residual FADD protein with FAS. Analysis of FAS-induced apoptosis in
patients' cells confirmed that the C105W mutant impairs apoptotic
function both in vitro and in vivo.
*FIELD* RF
1. Balachandran, S.; Thomas, E.; Barber, G. N.: A FADD-dependent
innate immune mechanism in mammalian cells. Nature 432: 401-405,
2004.
2. Bolze, A.; Byun, M.; McDonald, D.; Morgan, N. V.; Abhyankar, A.;
Premkumar, L.; Puel, A.; Bacon, C. M.; Rieux-Laucat, F.; Pang, K.;
Britland, A.; Abel, L.; Cant, A.; Maher, E. R.; Riedl, S. J.; Hambleton,
S.; Casanova, J.-L.: Whole-exome-sequencing-based discovery of human
FADD deficiency. Am. J. Hum. Genet. 87: 873-881, 2010.
3. Chinnaiyan, A. M.; O'Rourke, K.; Tewari, M.; Dixit, V. M.: FADD,
a novel death domain-containing protein, interacts with the death
domain of Fas and initiates apoptosis. Cell 81: 505-512, 1995.
4. Gregory-Evans, C. Y.; Moosajee, M.; Hodges, M. D.; Mackay, D. S.;
Game, L.; Vargesson, N.; Bloch-Zupan, A.; Ruschendorf, F.; Santos-Pinto,
L.; Wackens, G.; Gregory-Evans, K.: SNP genome scanning localizes
oto-dental syndrome to chromosome 11q13 and microdeletions at this
locus implicate FGF3 in dental and inner-ear disease and FADD in ocular
coloboma. Hum. Molec. Genet. 16: 2482-2493, 2007.
5. Kabra, N. H.; Kang, C.; Hsing, L. C.; Zhang, J.; Winoto, A.: T
cell-specific FADD-deficient mice: FADD is required for early T cell
development. Proc. Nat. Acad. Sci. 98: 6307-6312, 2001.
6. Kim, P. K. M.; Dutra, A. S.; Chandrasekharappa, S. C.; Puck, J.
M.: Genomic structure and mapping of human FADD, an intracellular
mediator of lymphocyte apoptosis. J. Immun. 157: 5461-5466, 1996.
7. Lee, H.-J.; Pyo, J.-O.; Oh, Y.; Kim, H.-J.; Hong, S.; Jeon, Y.-J.;
Kim, H.; Cho, D.-H.; Woo, H.-N.; Song, S.; Nam, J.-H.; Kim, H. J.;
Kim, K.-S.; Jung, Y.-K.: AK2 activates a novel apoptotic pathway
through formation of a complex with FADD and caspase-10. Nature Cell
Biol. 9: 1303-1310, 2007.
8. Li, S.; Zhang, L.; Yao, Q.; Li, L.; Dong, N.; Rong, J.; Gao, W.;
Ding, X.; Sun, L.; Chen, X.; Chen, S.; Shao, F.: Pathogen blocks
host death receptor signaling by arginine GlcNAcylation of death domains. Nature 501:
242-246, 2013.
9. Pearson, J. S.; Giogha, C.; Ong, S. Y.; Kennedy, C. L.; Kelly,
M.; Robinson, K. S.; Lung, T. W. F.; Mansell, A.; Riedmaier, P.; Oates,
C. V. L.; Zaid, A.; Muhlen, S.; and 13 others: A type III effector
antagonizes death receptor signalling during bacterial gut infection. Nature 501:
247-251, 2013.
10. Scott, F. L.; Stec, B.; Pop, C.; Dobaczewska, M. K.; Lee, J. J.;
Monosov, E.; Robinson, H.; Salvesen, G. S.; Schwarzenbacher, R.; Riedl,
S. J.: The Fas-FADD death domain complex structure unravels signalling
by receptor clustering. Nature 457: 1019-1022, 2009.
11. Welz, P.-S.; Wullaert, A.; Vlantis, K.; Kondylis, V.; Fernandez-Majada,
V.; Ermolaeva, M.; Kirsch, P.; Sterner-Kock, A.; van Loo, G.; Pasparakis,
M.: FADD prevents RIP3-mediated epithelial cell necrosis and chronic
intestinal inflammation. Nature 477: 330-334, 2011.
12. Yeh, W.-C.; de la Pompa, J. L.; McCurrach, M. E.; Shu, H.-B.;
Elia, A. J.; Shahinian, A.; Ng, M.; Wakeham, A.; Khoo, W.; Mitchell,
K.; El-Deiry, W. S.; Lowe, S. W.; Goeddel, D. V.; Mak, T. W.: FADD:
essential for embryo development and signaling from some, but not
all, inducers of apoptosis. Science 279: 1954-1958, 1998.
13. Zhang, H.; Zhou, X.; McQuade, T.; Li, J.; Chan, F. K.-M.; Zhang,
J.: Functional complementation between FADD and RIP1 in embryos and
lymphocytes. Nature 471: 373-376, 2011. Note: Erratum: Nature 483:
498 only, 2012.
14. Zhang, J.; Cado, D.; Chen, A.; Kabra, N. H.; Winoto, A.: Fas-mediated
apoptosis and activation-induced T-cell proliferation are defective
in mice lacking FADD/Mort1. Nature 392: 296-300, 1998.
*FIELD* CN
Ada Hamosh - updated: 12/12/2013
Ada Hamosh - updated: 12/11/2013
Ada Hamosh - updated: 11/22/2011
Ada Hamosh - updated: 6/7/2011
Marla J. F. O'Neill - updated: 2/16/2011
Marla J. F. O'Neill - updated: 11/30/2009
Ada Hamosh - updated: 3/10/2009
Patricia A. Hartz - updated: 10/28/2008
Ada Hamosh - updated: 12/10/2004
Victor A. McKusick - updated: 6/27/2001
Rebekah S. Rasooly - updated: 1/13/1999
*FIELD* CD
Victor A. McKusick: 3/20/1998
*FIELD* ED
alopez: 12/12/2013
alopez: 12/11/2013
alopez: 4/25/2012
alopez: 11/30/2011
alopez: 11/29/2011
terry: 11/22/2011
alopez: 6/14/2011
terry: 6/7/2011
wwang: 2/22/2011
terry: 2/16/2011
wwang: 12/17/2009
terry: 11/30/2009
alopez: 3/12/2009
terry: 3/10/2009
mgross: 10/28/2008
wwang: 5/15/2007
alopez: 12/15/2004
terry: 12/10/2004
alopez: 10/30/2001
cwells: 7/11/2001
terry: 6/27/2001
alopez: 5/12/1999
alopez: 1/14/1999
alopez: 1/13/1999
alopez: 1/5/1999
alopez: 12/18/1998
alopez: 3/20/1998
MIM
613759
*RECORD*
*FIELD* NO
613759
*FIELD* TI
#613759 INFECTIONS, RECURRENT, WITH ENCEPHALOPATHY, HEPATIC DYSFUNCTION, AND
CARDIOVASCULAR MALFORMATIONS
read more;;FADD DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
recurrent infections associated with encephalopathy, hepatic
dysfunction, and cardiovascular malformations is caused by homozygous
mutation in the FADD gene (602457) on chromosome 11q13.3.
CLINICAL FEATURES
Bolze et al. (2010) studied a large consanguineous Pakistani pedigree in
which a brother and 2 sisters and a female cousin suffered from
recurrent, stereotypical episodes of fever, encephalopathy, and mild
liver dysfunction involving modestly elevated transaminases without
cholestasis, metabolic derangement, or synthetic defects, sometimes
accompanied by generalized seizures that were difficult to control.
Episodes lasted several days, sometimes requiring intensive care.
Cranial imaging in 3 patients suggested cerebral atrophy, despite
recovery in 2 of them. For some of the episodes, it was possible to
identify a viral trigger, including varicella zoster virus,
measles-mumps-rubella (MMR) attenuated vaccine, parainfluenza virus, and
Epstein-Barr virus (EBV). One of the sisters died at 4 years of age
during such an episode, and the other sister and brother died of fatal
invasive pneumococcal disease at ages 4 months and 14 months,
respectively. Their affected cousin was alive at 2.75 years of age.
Howell-Jolly bodies were detected in 2 patients despite the presence of
a spleen, indicating functional hyposplenism. Two of the 4 patients had
congenital cardiovascular malformations: pulmonary atresia and a
ventricular septal defect in 1 sister, and a left-sided superior vena
cava that drained into the left atrium in the cousin. In the previous
generation, another 5 family members had died in childhood, 2 with
'epilepsy' and 2 from infection (pneumonia and measles, respectively),
suggesting that there may have been up to 9 family members with this
disorder over 2 generations. Laboratory findings in affected individuals
were similar to those seen in autoimmune lymphoproliferative syndrome
(ALPS; 601859), including high-circulating CD4(-)CD8(-)TCR-alpha-beta(+)
T-cell (DNT) counts, and elevated IL10 (124092) and FASL (TNFSF6;
134638) levels, but the Pakistani patients did not exhibit the clinical
features of ALPS.
MAPPING
In a large consanguineous Pakistani kindred with recurrent infections
accompanied by encephalopathy and hepatic dysfunction, Bolze et al.
(2010) combined homozygosity mapping with whole-exome sequencing and
identified 2 homozygous regions in patients that were heterozygous in
unaffected relatives: an 8-Mb interval on chromosome 11 and a 9-Mb
interval on chromosome 18. Sequencing identified only 1 nonsynonymous
variant within the candidate intervals that had not been previously
reported, on chromosome 11.
MOLECULAR GENETICS
In 2 sisters and their cousin from a large consanguineous Pakistani
pedigree, who had recurrent infections associated with encephalopathy,
hepatic dysfunction, and cardiovascular malformations, Bolze et al.
(2010) identified homozygosity for a missense mutation in the the FADD
gene (602457.0001). The mutation segregated with disease in the kindred
and was not found in 282 Pakistani controls. Based on the patients'
laboratory findings as well as in vitro and in vivo studies of FADD
deficiency, Bolze et al. (2010) concluded that the observed bacterial
infections result partly from functional hyposplenism, and the viral
infections from impaired interferon immunity.
*FIELD* RF
1. Bolze, A.; Byun, M.; McDonald, D.; Morgan, N. V.; Abhyankar, A.;
Premkumar, L.; Puel, A.; Bacon, C. M.; Rieux-Laucat, F.; Pang, K.;
Britland, A.; Abel, L.; Cant, A.; Maher, E. R.; Riedl, S. J.; Hambleton,
S.; Casanova, J.-L.: Whole-exome-sequencing-based discovery of human
FADD deficiency. Am. J. Hum. Genet. 87: 873-881, 2010.
*FIELD* CS
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Heart];
Ventricular septal defect;
[Vascular];
Superior vena cava left-sided, draining into left atrium;
Pulmonary atresia
ABDOMEN:
[Liver];
Liver dysfunction, mild;
Transaminases mildly elevated;
[Spleen];
Functional hyposplenism;
Howell-Jolly bodies present
NEUROLOGIC:
[Central nervous system];
Encephalopathy;
Cerebral atrophy;
Seizures
IMMUNOLOGY:
Recurrent infections;
Increased number of CD4(-)CD8(-)TCR-alpha-beta(+) T cells
LABORATORY ABNORMALITIES:
Increased Fas ligand;
Increased interleukin 10
MOLECULAR BASIS:
Caused by mutation in the Fas-associated via death domain gene (FADD,
602457.0001)
*FIELD* CD
Marla J. F. O'Neill: 2/3/2012
*FIELD* ED
joanna: 02/03/2012
*FIELD* CD
Marla J. F. O'Neill: 2/22/2011
*FIELD* ED
carol: 03/10/2011
terry: 3/4/2011
wwang: 2/22/2011
*RECORD*
*FIELD* NO
613759
*FIELD* TI
#613759 INFECTIONS, RECURRENT, WITH ENCEPHALOPATHY, HEPATIC DYSFUNCTION, AND
CARDIOVASCULAR MALFORMATIONS
read more;;FADD DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
recurrent infections associated with encephalopathy, hepatic
dysfunction, and cardiovascular malformations is caused by homozygous
mutation in the FADD gene (602457) on chromosome 11q13.3.
CLINICAL FEATURES
Bolze et al. (2010) studied a large consanguineous Pakistani pedigree in
which a brother and 2 sisters and a female cousin suffered from
recurrent, stereotypical episodes of fever, encephalopathy, and mild
liver dysfunction involving modestly elevated transaminases without
cholestasis, metabolic derangement, or synthetic defects, sometimes
accompanied by generalized seizures that were difficult to control.
Episodes lasted several days, sometimes requiring intensive care.
Cranial imaging in 3 patients suggested cerebral atrophy, despite
recovery in 2 of them. For some of the episodes, it was possible to
identify a viral trigger, including varicella zoster virus,
measles-mumps-rubella (MMR) attenuated vaccine, parainfluenza virus, and
Epstein-Barr virus (EBV). One of the sisters died at 4 years of age
during such an episode, and the other sister and brother died of fatal
invasive pneumococcal disease at ages 4 months and 14 months,
respectively. Their affected cousin was alive at 2.75 years of age.
Howell-Jolly bodies were detected in 2 patients despite the presence of
a spleen, indicating functional hyposplenism. Two of the 4 patients had
congenital cardiovascular malformations: pulmonary atresia and a
ventricular septal defect in 1 sister, and a left-sided superior vena
cava that drained into the left atrium in the cousin. In the previous
generation, another 5 family members had died in childhood, 2 with
'epilepsy' and 2 from infection (pneumonia and measles, respectively),
suggesting that there may have been up to 9 family members with this
disorder over 2 generations. Laboratory findings in affected individuals
were similar to those seen in autoimmune lymphoproliferative syndrome
(ALPS; 601859), including high-circulating CD4(-)CD8(-)TCR-alpha-beta(+)
T-cell (DNT) counts, and elevated IL10 (124092) and FASL (TNFSF6;
134638) levels, but the Pakistani patients did not exhibit the clinical
features of ALPS.
MAPPING
In a large consanguineous Pakistani kindred with recurrent infections
accompanied by encephalopathy and hepatic dysfunction, Bolze et al.
(2010) combined homozygosity mapping with whole-exome sequencing and
identified 2 homozygous regions in patients that were heterozygous in
unaffected relatives: an 8-Mb interval on chromosome 11 and a 9-Mb
interval on chromosome 18. Sequencing identified only 1 nonsynonymous
variant within the candidate intervals that had not been previously
reported, on chromosome 11.
MOLECULAR GENETICS
In 2 sisters and their cousin from a large consanguineous Pakistani
pedigree, who had recurrent infections associated with encephalopathy,
hepatic dysfunction, and cardiovascular malformations, Bolze et al.
(2010) identified homozygosity for a missense mutation in the the FADD
gene (602457.0001). The mutation segregated with disease in the kindred
and was not found in 282 Pakistani controls. Based on the patients'
laboratory findings as well as in vitro and in vivo studies of FADD
deficiency, Bolze et al. (2010) concluded that the observed bacterial
infections result partly from functional hyposplenism, and the viral
infections from impaired interferon immunity.
*FIELD* RF
1. Bolze, A.; Byun, M.; McDonald, D.; Morgan, N. V.; Abhyankar, A.;
Premkumar, L.; Puel, A.; Bacon, C. M.; Rieux-Laucat, F.; Pang, K.;
Britland, A.; Abel, L.; Cant, A.; Maher, E. R.; Riedl, S. J.; Hambleton,
S.; Casanova, J.-L.: Whole-exome-sequencing-based discovery of human
FADD deficiency. Am. J. Hum. Genet. 87: 873-881, 2010.
*FIELD* CS
INHERITANCE:
Autosomal recessive
CARDIOVASCULAR:
[Heart];
Ventricular septal defect;
[Vascular];
Superior vena cava left-sided, draining into left atrium;
Pulmonary atresia
ABDOMEN:
[Liver];
Liver dysfunction, mild;
Transaminases mildly elevated;
[Spleen];
Functional hyposplenism;
Howell-Jolly bodies present
NEUROLOGIC:
[Central nervous system];
Encephalopathy;
Cerebral atrophy;
Seizures
IMMUNOLOGY:
Recurrent infections;
Increased number of CD4(-)CD8(-)TCR-alpha-beta(+) T cells
LABORATORY ABNORMALITIES:
Increased Fas ligand;
Increased interleukin 10
MOLECULAR BASIS:
Caused by mutation in the Fas-associated via death domain gene (FADD,
602457.0001)
*FIELD* CD
Marla J. F. O'Neill: 2/3/2012
*FIELD* ED
joanna: 02/03/2012
*FIELD* CD
Marla J. F. O'Neill: 2/22/2011
*FIELD* ED
carol: 03/10/2011
terry: 3/4/2011
wwang: 2/22/2011