RBCC Red Blood Cell Collection

PSMB8 (LMP7, PSMB5i, RING10, Y2) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Proteasome subunit beta type-8; 3.4.25.1 (Low molecular mass protein 7; Macropain subunit C13; Multicatalytic endopeptidase complex subunit C13; Proteasome component C13; Proteasome subunit beta-5i; Really interesting new gene 10 protein; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P28062
ID PSB8_HUMAN Reviewed; 276 AA.
AC P28062; B0UZC0; Q29824; Q5JNW6; Q5QNR8; Q96J48;
DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
read moreDT 31-MAY-2011, sequence version 3.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Proteasome subunit beta type-8;
DE EC=3.4.25.1;
DE AltName: Full=Low molecular mass protein 7;
DE AltName: Full=Macropain subunit C13;
DE AltName: Full=Multicatalytic endopeptidase complex subunit C13;
DE AltName: Full=Proteasome component C13;
DE AltName: Full=Proteasome subunit beta-5i;
DE AltName: Full=Really interesting new gene 10 protein;
DE Flags: Precursor;
GN Name=PSMB8; Synonyms=LMP7, PSMB5i, RING10, Y2;
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 [GENOMIC DNA].
RX PubMed=8458375; DOI=10.1002/eji.1830230414;
RA Glynne R., Kerr L.A., Mockridge I., Beck S., Kelly A., Trowsdale J.;
RT "The major histocompatibility complex-encoded proteasome component
RT LMP7: alternative first exons and post-translational processing.";
RL Eur. J. Immunol. 23:860-866(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1453454; DOI=10.1016/0022-2836(92)90832-5;
RA Beck S., Kelly A., Radley E., Khurshid F., Alderton R.P.,
RA Trowsdale J.;
RT "DNA sequence analysis of 66 kb of the human MHC class II region
RT encoding a cluster of genes for antigen processing.";
RL J. Mol. Biol. 228:433-441(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=1922342; DOI=10.1038/353357a0;
RA Glynne R., Powis S.H., Beck S., Kelly A., Kerr L.A., Trowsdale J.;
RT "A proteasome-related gene between the two ABC transporter loci in the
RT class II region of the human MHC.";
RL Nature 353:357-360(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1429565;
RA Fruh K., Yang Y., Arnold D., Chambers J., Wu L., Waters J.B.,
RA Spies T., Peterson P.A.;
RT "Alternative exon usage and processing of the major histocompatibility
RT complex-encoded proteasome subunits.";
RL J. Biol. Chem. 267:22131-22140(1992).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8344725; DOI=10.1007/BF00210482;
RA Meinhardt T., Graf U., Hammerling G.J.;
RT "Different genomic structure of mouse and human Lmp7 genes:
RT characterization of MHC-encoded proteasome genes.";
RL Immunogenetics 38:373-379(1993).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8568858; DOI=10.1006/jmbi.1996.0001;
RA Beck S., Abdulla S., Alderton R.P., Glynne R.J., Gut I.G.,
RA Hosking L.K., Jackson A., Kelly A., Newell W.R., Sanseau P.,
RA Radley E., Thorpe K.L., Trowsdale J.;
RT "Evolutionary dynamics of non-coding sequences within the class II
RT region of the human MHC.";
RL J. Mol. Biol. 255:1-13(1996).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ALLELE LMP7C), AND VARIANT LYS-49.
RA Maksymowych W.P.;
RT "Sequence analysis of the HLA-linked LMP7 gene.";
RL Submitted (NOV-1994) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
RA Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [9]
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Skin;
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 [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 191-269.
RC TISSUE=Blood;
RX PubMed=9157092; DOI=10.1016/0198-8859(95)00172-7;
RA Kim T.G., Lee Y.H., Choi H.B., Han H.;
RT "Two newly discovered alleles of major histocompatibility complex-
RT encoded LMP7 in Korean populations.";
RL Hum. Immunol. 46:61-64(1996).
RN [12]
RP FUNCTION.
RX PubMed=8163024; DOI=10.1016/0014-5793(94)80612-8;
RA Akiyama K., Kagawa S., Tamura T., Shimbara N., Takashina M.,
RA Kristensen P., Hendil K.B., Tanaka K., Ichihara A.;
RT "Replacement of proteasome subunits X and Y by LMP7 and LMP2 induced
RT by interferon-gamma for acquirement of the functional diversity
RT responsible for antigen processing.";
RL FEBS Lett. 343:85-88(1994).
RN [13]
RP INDUCTION.
RX PubMed=8663318; DOI=10.1074/jbc.271.29.17275;
RA Gaczynska M., Goldberg A.L., Tanaka K., Hendil K.B., Rock K.L.;
RT "Proteasome subunits X and Y alter peptidase activities in opposite
RT ways to the interferon-gamma-induced subunits LMP2 and LMP7.";
RL J. Biol. Chem. 271:17275-17280(1996).
RN [14]
RP INDUCTION BY TNF AND IFNG.
RX PubMed=11493458; DOI=10.1182/blood.V98.4.1108;
RA Hallermalm K., Seki K., Wei C., Castelli C., Rivoltini L.,
RA Kiessling R., Levitskaya J.;
RT "Tumor necrosis factor-alpha induces coordinated changes in major
RT histocompatibility class I presentation pathway, resulting in
RT increased stability of class I complexes at the cell surface.";
RL Blood 98:1108-1115(2001).
RN [15]
RP DEVELOPMENTAL STAGE.
RX PubMed=11717192; DOI=10.1093/intimm/13.12.1515;
RA Li J., Schuler-Thurner B., Schuler G., Huber C., Seliger B.;
RT "Bipartite regulation of different components of the MHC class I
RT antigen-processing machinery during dendritic cell maturation.";
RL Int. Immunol. 13:1515-1523(2001).
RN [16]
RP INTERACTION WITH HIV-1 TAT.
RX PubMed=14550573; DOI=10.1016/S0014-5793(03)01025-1;
RA Apcher G.S., Heink S., Zantopf D., Kloetzel P.-M., Schmid H.-P.,
RA Mayer R.J., Krueger E.;
RT "Human immunodeficiency virus-1 Tat protein interacts with distinct
RT proteasomal alpha and beta subunits.";
RL FEBS Lett. 553:200-204(2003).
RN [17]
RP INDUCTION BY TETRODOTOXIN.
RX PubMed=15501285; DOI=10.1016/j.toxicon.2004.07.018;
RA Raghavendra Prasad H.S., Qi Z., Srinivasan K.N., Gopalakrishnakone P.;
RT "Potential effects of tetrodotoxin exposure to human glial cells
RT postulated using microarray approach.";
RL Toxicon 44:597-608(2004).
RN [18]
RP INDUCTION BY IFNG AND IRF1.
RX PubMed=15907481; DOI=10.1016/j.febslet.2005.04.012;
RA Namiki S., Nakamura T., Oshima S., Yamazaki M., Sekine Y.,
RA Tsuchiya K., Okamoto R., Kanai T., Watanabe M.;
RT "IRF-1 mediates upregulation of LMP7 by IFN-gamma and concerted
RT expression of immunosubunits of the proteasome.";
RL FEBS Lett. 579:2781-2787(2005).
RN [19]
RP INTERACTION WITH TAP1.
RX PubMed=15488952; DOI=10.1016/j.molimm.2004.07.005;
RA Begley G.S., Horvath A.R., Taylor J.C., Higgins C.F.;
RT "Cytoplasmic domains of the transporter associated with antigen
RT processing and P-glycoprotein interact with subunits of the
RT proteasome.";
RL Mol. Immunol. 42:137-141(2005).
RN [20]
RP INTERACTION WITH POMP.
RX PubMed=15944226; DOI=10.1073/pnas.0501711102;
RA Heink S., Ludwig D., Kloetzel P.-M., Krueger E.;
RT "IFN-gamma-induced immune adaptation of the proteasome system is an
RT accelerated and transient response.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:9241-9246(2005).
RN [21]
RP FUNCTION.
RX PubMed=16423992; DOI=10.1158/0008-5472.CAN-05-2872;
RA Heink S., Fricke B., Ludwig D., Kloetzel P.M., Krueger E.;
RT "Tumor cell lines expressing the proteasome subunit isoform LMP7E1
RT exhibit immunoproteasome deficiency.";
RL Cancer Res. 66:649-652(2006).
RN [22]
RP INDUCTION BY HEAT SHOCK.
RX PubMed=17142736;
RA Callahan M.K., Wohlfert E.A., Menoret A., Srivastava P.K.;
RT "Heat shock up-regulates lmp2 and lmp7 and enhances presentation of
RT immunoproteasome-dependent epitopes.";
RL J. Immunol. 177:8393-8399(2006).
RN [23]
RP INDUCTION.
RX PubMed=17262812; DOI=10.1002/ibd.20110;
RA Wu F., Dassopoulos T., Cope L., Maitra A., Brant S.R., Harris M.L.,
RA Bayless T.M., Parmigiani G., Chakravarti S.;
RT "Genome-wide gene expression differences in Crohn's disease and
RT ulcerative colitis from endoscopic pinch biopsies: insights into
RT distinctive pathogenesis.";
RL Inflamm. Bowel Dis. 13:807-821(2007).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-5 (ISOFORM 2), AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [25]
RP INDUCTION BY IFNG, AND FUNCTION.
RX PubMed=19443843; DOI=10.1161/ATVBAHA.109.189407;
RA Yang Z., Gagarin D., St Laurent G. III, Hammell N., Toma I., Hu C.A.,
RA Iwasa A., McCaffrey T.A.;
RT "Cardiovascular inflammation and lesion cell apoptosis: a novel
RT connection via the interferon-inducible immunoproteasome.";
RL Arterioscler. Thromb. Vasc. Biol. 29:1213-1219(2009).
RN [26]
RP INDUCTION.
RX PubMed=19619915; DOI=10.1016/j.imbio.2009.06.020;
RA Eisemann J., Prechtel A.T., Muehl-Zuerbes P., Steinkasserer A.,
RA Kummer M.;
RT "Herpes simplex virus type I infection of mature dendritic cells leads
RT to reduced LMP7-mRNA-expression levels.";
RL Immunobiology 214:861-867(2009).
RN [27]
RP INDUCTION BY PR-957.
RX PubMed=19525961; DOI=10.1038/nm.1978;
RA Muchamuel T., Basler M., Aujay M.A., Suzuki E., Kalim K.W., Lauer C.,
RA Sylvain C., Ring E.R., Shields J., Jiang J., Shwonek P., Parlati F.,
RA Demo S.D., Bennett M.K., Kirk C.J., Groettrup M.;
RT "A selective inhibitor of the immunoproteasome subunit LMP7 blocks
RT cytokine production and attenuates progression of experimental
RT arthritis.";
RL Nat. Med. 15:781-787(2009).
RN [28]
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 [29]
RP FUNCTION IN ADIPOCYTE DIFFERENTIATION, VARIANT NKJO VAL-201, AND
RP CHARACTERIZATION OF VARIANT NKJO VAL-201.
RX PubMed=21881205; DOI=10.1172/JCI58414;
RA Kitamura A., Maekawa Y., Uehara H., Izumi K., Kawachi I.,
RA Nishizawa M., Toyoshima Y., Takahashi H., Standley D.M., Tanaka K.,
RA Hamazaki J., Murata S., Obara K., Toyoshima I., Yasutomo K.;
RT "A mutation in the immunoproteasome subunit PSMB8 causes
RT autoinflammation and lipodystrophy in humans.";
RL J. Clin. Invest. 121:4150-4160(2011).
RN [30]
RP VARIANT NKJO MET-75, AND CHARACTERIZATION OF VARIANT NKJO MET-75.
RX PubMed=21129723; DOI=10.1016/j.ajhg.2010.10.031;
RA Agarwal A.K., Xing C., DeMartino G.N., Mizrachi D., Hernandez M.D.,
RA Sousa A.B., Martinez de Villarreal L., dos Santos H.G., Garg A.;
RT "PSMB8 encoding the beta5i proteasome subunit is mutated in joint
RT contractures, muscle atrophy, microcytic anemia, and panniculitis-
RT induced lipodystrophy syndrome.";
RL Am. J. Hum. Genet. 87:866-872(2010).
RN [31]
RP INVOLVEMENT OF VARIANT NKJO MET-75 IN CANDLE SYNDROME.
RX PubMed=21953331; DOI=10.1002/art.33368;
RA Liu Y., Ramot Y., Torrelo A., Paller A.S., Si N., Babay S., Kim P.W.,
RA Sheikh A., Lee C.C., Chen Y., Vera A., Zhang X., Goldbach-Mansky R.,
RA Zlotogorski A.;
RT "Mutations in proteasome subunit beta type 8 cause chronic atypical
RT neutrophilic dermatosis with lipodystrophy and elevated temperature
RT with evidence of genetic and phenotypic heterogeneity.";
RL Arthritis Rheum. 64:895-907(2012).
RN [32]
RP VARIANT NKJO VAL-201, AND CHARACTERIZATION OF VARIANT NKJO VAL-201.
RX PubMed=21852578; DOI=10.1073/pnas.1106015108;
RA Arima K., Kinoshita A., Mishima H., Kanazawa N., Kaneko T.,
RA Mizushima T., Ichinose K., Nakamura H., Tsujino A., Kawakami A.,
RA Matsunaka M., Kasagi S., Kawano S., Kumagai S., Ohmura K., Mimori T.,
RA Hirano M., Ueno S., Tanaka K., Tanaka M., Toyoshima I., Sugino H.,
RA Yamakawa A., Tanaka K., Niikawa N., Furukawa F., Murata S., Eguchi K.,
RA Ida H., Yoshiura K.;
RT "Proteasome assembly defect due to a proteasome subunit beta type 8
RT (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-
RT Nishimura syndrome.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:14914-14919(2011).
CC -!- FUNCTION: The proteasome is a multicatalytic proteinase complex
CC which is characterized by its ability to cleave peptides with Arg,
CC Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or
CC slightly basic pH. The proteasome has an ATP-dependent proteolytic
CC activity. This subunit is involved in antigen processing to
CC generate class I binding peptides. Replacement of PSMB5 by PSMB8
CC increases the capacity of the immunoproteasome to cleave model
CC peptides after hydrophobic and basic residues. Acts as a major
CC component of interferon gamma-induced sensitivity. Plays a key
CC role in apoptosis via the degradation of the apoptotic inhibitor
CC MCL1. May be involved in the inflammatory response pathway. In
CC cancer cells, substitution of isoform 1 (E2) by isoform 2 (E1)
CC results in immunoproteasome deficiency. Required for the
CC differentiation of preadipocytes into adipocytes.
CC -!- CATALYTIC ACTIVITY: Cleavage of peptide bonds with very broad
CC specificity.
CC -!- SUBUNIT: The 26S proteasome consists of a 20S proteasome core and
CC two 19S regulatory subunits. The 20S proteasome core is composed
CC of 28 subunits that are arranged in four stacked rings, resulting
CC in a barrel-shaped structure. The two end rings are each formed by
CC seven alpha subunits, and the two central rings are each formed by
CC seven beta subunits. The catalytic chamber with the active sites
CC is on the inside of the barrel. This subunit is part of the
CC immunoproteasome where it displaces the equivalent housekeeping
CC subunit PSMB5. Component of the spermatoproteasome, a form of the
CC proteasome specifically found in testis. Directly interacts with
CC POMP. Interacts with HIV-1 TAT protein. Interacts with TAP1.
CC -!- INTERACTION:
CC P27958:- (xeno); NbExp=4; IntAct=EBI-372294, EBI-3649474;
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity). Nucleus (By
CC similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Comment=Additional isoforms seem to exist;
CC Name=1; Synonyms=LMP7B, LMP7-E2;
CC IsoId=P28062-1; Sequence=Displayed;
CC Name=2; Synonyms=LMP7A, LMP7-E1;
CC IsoId=P28062-2; Sequence=VSP_005287;
CC Note=Contains a phosphothreonine at position 5;
CC -!- DEVELOPMENTAL STAGE: Highly expressed in immature dendritic cells
CC (at protein level).
CC -!- INDUCTION: Up-regulated by IFNG/IFN-gamma and IRF1 (at protein
CC level). Up-regulated by TNF (at protein level). Up-regulated by
CC tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel
CC disease (CD). Down-regulated by the selective inhibitor PR-957.
CC Down-regulated in mature dendritic cells by HSV-1 infection. Up-
CC regulated by heat shock treatment.
CC -!- PTM: Autocleaved. The resulting N-terminal Thr residue of the
CC mature subunit is responsible for the nucleophile proteolytic
CC activity (By similarity).
CC -!- DISEASE: Nakajo syndrome (NKJO) [MIM:256040]: An autosomal
CC recessive autoinflammatory disorder characterized by early
CC childhood onset of recurrent fever, joint stiffness and severe
CC contractures of the hands and feet, and erythematous skin lesions
CC with subsequent development of lipodystrophy and laboratory
CC evidence of immune dysregulation. Accompanying features may
CC include muscle weakness and atrophy, hepatosplenomegaly, and
CC microcytic anemia. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Note=Mutation Met-75 has been found in chronic atypical
CC neutrophilic dermatosis with lipodystrophy and elevated
CC temperature syndrome (CANDLE syndrome). CANDLE patients have some
CC overlapping features with NKJO patients, including a cutaneous
CC eruption and lipodystrophy. They show a characteristic
CC neutrophilic dermatosis with a mononuclear interstitial infiltrate
CC in the dermis that seems pathognomonic for CANDLE syndrome
CC (PubMed:21953331).
CC -!- SIMILARITY: Belongs to the peptidase T1B family.
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DR EMBL; X66401; CAA47026.1; -; Genomic_DNA.
DR EMBL; X62598; CAA44482.1; -; mRNA.
DR EMBL; Z14982; CAA78705.1; -; Genomic_DNA.
DR EMBL; Z14982; CAA78706.1; -; Genomic_DNA.
DR EMBL; L11045; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; X87344; CAA60786.1; -; Genomic_DNA.
DR EMBL; X87344; CAA60787.1; -; Genomic_DNA.
DR EMBL; U17496; AAA56777.1; -; mRNA.
DR EMBL; U17497; AAA56778.1; -; mRNA.
DR EMBL; AL671681; CAI17712.1; -; Genomic_DNA.
DR EMBL; AL671681; CAI17713.1; -; Genomic_DNA.
DR EMBL; AL669918; CAI18138.1; -; Genomic_DNA.
DR EMBL; AL669918; CAI18139.1; -; Genomic_DNA.
DR EMBL; AL935043; CAI18623.1; -; Genomic_DNA.
DR EMBL; AL935043; CAI18625.1; -; Genomic_DNA.
DR EMBL; BX682530; CAM25945.1; -; Genomic_DNA.
DR EMBL; BX088556; CAM25945.1; JOINED; Genomic_DNA.
DR EMBL; BX682530; CAM25947.1; -; Genomic_DNA.
DR EMBL; BX088556; CAM25947.1; JOINED; Genomic_DNA.
DR EMBL; BX088556; CAM26261.1; -; Genomic_DNA.
DR EMBL; BX682530; CAM26261.1; JOINED; Genomic_DNA.
DR EMBL; BX088556; CAM26262.1; -; Genomic_DNA.
DR EMBL; BX682530; CAM26262.1; JOINED; Genomic_DNA.
DR EMBL; CT009502; CAQ07779.1; -; Genomic_DNA.
DR EMBL; CT009502; CAQ07781.1; -; Genomic_DNA.
DR EMBL; BX927138; CAQ08445.1; -; Genomic_DNA.
DR EMBL; BX927138; CAQ08448.1; -; Genomic_DNA.
DR EMBL; CR762476; CAQ08492.1; -; Genomic_DNA.
DR EMBL; CR762476; CAQ08494.1; -; Genomic_DNA.
DR EMBL; CR753889; CAQ10284.1; -; Genomic_DNA.
DR EMBL; CR753889; CAQ10286.1; -; Genomic_DNA.
DR EMBL; CH471081; EAX03644.1; -; Genomic_DNA.
DR EMBL; CH471081; EAX03645.1; -; Genomic_DNA.
DR EMBL; BC001114; AAH01114.1; -; mRNA.
DR EMBL; U32863; AAA80235.1; -; Genomic_DNA.
DR EMBL; U32862; AAA80234.1; -; Genomic_DNA.
DR PIR; A44324; A44324.
DR PIR; C44324; C44324.
DR PIR; G01564; G01564.
DR PIR; G02018; G02018.
DR RefSeq; NP_004150.1; NM_004159.4.
DR RefSeq; NP_683720.2; NM_148919.3.
DR UniGene; Hs.180062; -.
DR ProteinModelPortal; P28062; -.
DR SMR; P28062; 73-273.
DR IntAct; P28062; 8.
DR MINT; MINT-3010850; -.
DR STRING; 9606.ENSP00000402406; -.
DR BindingDB; P28062; -.
DR ChEMBL; CHEMBL2364701; -.
DR MEROPS; T01.015; -.
DR PhosphoSite; P28062; -.
DR DMDM; 1172602; -.
DR PaxDb; P28062; -.
DR PRIDE; P28062; -.
DR DNASU; 5696; -.
DR Ensembl; ENST00000374881; ENSP00000364015; ENSG00000204264.
DR Ensembl; ENST00000374882; ENSP00000364016; ENSG00000204264.
DR Ensembl; ENST00000383236; ENSP00000372723; ENSG00000206298.
DR Ensembl; ENST00000383238; ENSP00000372725; ENSG00000206298.
DR Ensembl; ENST00000416134; ENSP00000397057; ENSG00000235715.
DR Ensembl; ENST00000416564; ENSP00000408825; ENSG00000226201.
DR Ensembl; ENST00000421445; ENSP00000402406; ENSG00000236443.
DR Ensembl; ENST00000429645; ENSP00000394155; ENSG00000226201.
DR Ensembl; ENST00000435978; ENSP00000414731; ENSG00000231631.
DR Ensembl; ENST00000436627; ENSP00000392693; ENSG00000230669.
DR Ensembl; ENST00000438442; ENSP00000404585; ENSG00000231631.
DR Ensembl; ENST00000441960; ENSP00000407539; ENSG00000230034.
DR Ensembl; ENST00000452573; ENSP00000412618; ENSG00000236443.
DR Ensembl; ENST00000455660; ENSP00000406797; ENSG00000230669.
DR Ensembl; ENST00000457261; ENSP00000414770; ENSG00000235715.
DR Ensembl; ENST00000546794; ENSP00000448520; ENSG00000230034.
DR GeneID; 5696; -.
DR KEGG; hsa:5696; -.
DR UCSC; uc003oce.3; human.
DR CTD; 5696; -.
DR GeneCards; GC06M032808; -.
DR GeneCards; GC06Mi32792; -.
DR GeneCards; GC06Mj32730; -.
DR GeneCards; GC06Mk32786; -.
DR GeneCards; GC06Ml32962; -.
DR GeneCards; GC06Mm32841; -.
DR GeneCards; GC06Mn32737; -.
DR GeneCards; GC06Mo32898; -.
DR HGNC; HGNC:9545; PSMB8.
DR HPA; HPA046995; -.
DR HPA; HPA050327; -.
DR MIM; 177046; gene.
DR MIM; 256040; phenotype.
DR neXtProt; NX_P28062; -.
DR Orphanet; 325004; CANDLE syndrome.
DR Orphanet; 324999; JMP syndrome.
DR Orphanet; 2615; Nakajo-Nishimura syndrome.
DR PharmGKB; PA33890; -.
DR eggNOG; COG0638; -.
DR HOGENOM; HOG000091082; -.
DR HOVERGEN; HBG108297; -.
DR InParanoid; P28062; -.
DR KO; K02740; -.
DR OMA; MQPTEFL; -.
DR PhylomeDB; P28062; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_13505; Proteasome mediated degradation of PAK-2p34.
DR Reactome; REACT_21257; Metabolism of RNA.
DR Reactome; REACT_21300; Mitotic M-M/G1 phases.
DR Reactome; REACT_383; DNA Replication.
DR Reactome; REACT_578; Apoptosis.
DR Reactome; REACT_6850; Cdc20:Phospho-APC/C mediated degradation of Cyclin A.
DR Reactome; REACT_6900; Immune System.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; PSMB8; human.
DR GeneWiki; PSMB8; -.
DR GenomeRNAi; 5696; -.
DR NextBio; 22126; -.
DR PRO; PR:P28062; -.
DR ArrayExpress; P28062; -.
DR Bgee; P28062; -.
DR CleanEx; HS_PSMB8; -.
DR Genevestigator; P28062; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005839; C:proteasome core complex; ISS:UniProtKB.
DR GO; GO:1990111; C:spermatoproteasome complex; ISS:UniProtKB.
DR GO; GO:0004298; F:threonine-type endopeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0031145; P:anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process; TAS:Reactome.
DR GO; GO:0002479; P:antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent; TAS:Reactome.
DR GO; GO:0006915; P:apoptotic process; TAS:Reactome.
DR GO; GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; TAS:Reactome.
DR GO; GO:0045444; P:fat cell differentiation; IMP:UniProtKB.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; TAS:Reactome.
DR GO; GO:0010467; P:gene expression; TAS:Reactome.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0016071; P:mRNA metabolic process; TAS:Reactome.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:Reactome.
DR GO; GO:0051436; P:negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle; TAS:Reactome.
DR GO; GO:0051437; P:positive regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle; TAS:Reactome.
DR GO; GO:0000209; P:protein polyubiquitination; TAS:Reactome.
DR GO; GO:0006521; P:regulation of cellular amino acid metabolic process; TAS:Reactome.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0016032; P:viral process; TAS:Reactome.
DR InterPro; IPR000243; Pept_T1A_subB.
DR InterPro; IPR016050; Proteasome_bsu_CS.
DR InterPro; IPR001353; Proteasome_sua/b.
DR InterPro; IPR023333; Proteasome_suB-type.
DR Pfam; PF00227; Proteasome; 1.
DR PRINTS; PR00141; PROTEASOME.
DR PROSITE; PS00854; PROTEASOME_BETA_1; 1.
DR PROSITE; PS51476; PROTEASOME_BETA_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Cytoplasm; Differentiation;
KW Disease mutation; Host-virus interaction; Hydrolase; Immunity;
KW Nucleus; Phosphoprotein; Polymorphism; Protease; Proteasome;
KW Reference proteome; Threonine protease; Zymogen.
FT PROPEP 1 72 Removed in mature form (By similarity).
FT /FTId=PRO_0000026597.
FT CHAIN 73 276 Proteasome subunit beta type-8.
FT /FTId=PRO_0000026598.
FT ACT_SITE 73 73 Nucleophile (By similarity).
FT SITE 72 73 Cleavage; by autocatalysis (By
FT similarity).
FT VAR_SEQ 1 49 MALLDVCGAPRGQRPESALPVAGSGRRSDPGHYSFSMRSPE
FT LALPRGMQ -> MLIGTPTPRDTTPSSWLTSSLLVEAAPLD
FT DTTLPTPVSSGCPGLE (in isoform 2).
FT /FTId=VSP_005287.
FT VARIANT 8 8 G -> R (in LMP7C; dbSNP:rs114772012).
FT /FTId=VAR_006488.
FT VARIANT 30 32 PGH -> RPD (in LPM7C).
FT /FTId=VAR_006489.
FT VARIANT 49 49 Q -> K (in dbSNP:rs2071543).
FT /FTId=VAR_065204.
FT VARIANT 74 74 T -> S (in dbSNP:rs17220206).
FT /FTId=VAR_057046.
FT VARIANT 75 75 T -> M (in NKJO; also found in patients
FT with CANDLE syndrome; markedly decreased
FT chymotrypsin-like activity consistent
FT with a decrease in proteasomal activity
FT and loss of function).
FT /FTId=VAR_065291.
FT VARIANT 201 201 G -> V (in NKJO; affects immunoproteasome
FT assembly; reduced proteasome levels;
FT reduced chymotrypsin-like activity
FT consistent with a decrease in proteasomal
FT activity).
FT /FTId=VAR_066449.
SQ SEQUENCE 276 AA; 30354 MW; 4F689501677DBD44 CRC64;
MALLDVCGAP RGQRPESALP VAGSGRRSDP GHYSFSMRSP ELALPRGMQP TEFFQSLGGD
GERNVQIEMA HGTTTLAFKF QHGVIAAVDS RASAGSYISA LRVNKVIEIN PYLLGTMSGC
AADCQYWERL LAKECRLYYL RNGERISVSA ASKLLSNMMC QYRGMGLSMG SMICGWDKKG
PGLYYVDEHG TRLSGNMFST GSGNTYAYGV MDSGYRPNLS PEEAYDLGRR AIAYATHRDS
YSGGVVNMYH MKEDGWVKVE STDVSDLLHQ YREANQ
//

MIM 177046
*RECORD*
*FIELD* NO
177046
*FIELD* TI
*177046 PROTEASOME SUBUNIT, BETA-TYPE, 8; PSMB8
;;LARGE MULTIFUNCTIONAL PROTEASE 7; LMP7;;
read morePROTEASOME-RELATED GENE 7;;
RING10;;
PROTEASOME SUBUNIT BETA-5I
*FIELD* TX

DESCRIPTION

The immunoproteasome, a distinct class of proteasome found predominantly
in monocytes and lymphocytes, shapes the antigenic repertoire presented
on major histocompatibility complex (MHC) class I molecules. PSMB8
encodes the chymotrypsin-like catalytic subunit of the immunoproteasome
(Muchamuel et al., 2009).

GENE STRUCTURE

Agarwal et al. (2010) noted that the PSMB8 gene contains 6 exons with
alternative splicing of exons 1A and 1B.

MAPPING

Antigen processing involves the generation of peptides from cytosolic
proteins and their transport into the endoplasmic reticulum, where they
associate with MHC class I molecules. Two genes have been identified in
the MHC class II region, TAP1 (170260) and TAP2 (170261), that are
thought to encode the peptide transport proteins. Glynne et al. (1991)
reported a proteasome-related sequence, RING10, mapping between the
transporter genes on chromosome 6p21.3.

GENE FUNCTION

Muchamuel et al. (2009) showed that PR-957, a selective inhibitor of
LMP7, blocked presentation of MHC class I-restricted antigens in vitro
and in vivo. PR-957 also blocked production of IL23 (see 605580) by
activated monocytes and IL2 (147680) and IFNG (147570) by T cells. In
mouse models, PR-957 reversed signs of rheumatoid arthritis (RA; 180300)
and cellular infiltration, cytokine production, and autoantibody levels.
Muchamuel et al. (2009) concluded that LMP7 has a role in controlling
pathogenic immune responses and may be a target in autoimmune disorders.

Incorporation of the proteasome beta subunits into the maturing
proteasome frequently requires proteolytic removal of a prosequence by
proteolytically active subunits. By following the incorporation of
mutant human LMP7 into the 20S proteasome, Witt et al. (2000) showed
that the LMP7 prosequence was not essential for incorporation of LMP7
into the maturing proteasome, but it increased the efficiency of LMP7
incorporation and proteasome maturation.

MOLECULAR GENETICS

Deng et al. (1995) found evidence suggesting that LMP genes have effects
on susceptibility to insulin-dependent diabetes mellitus (IDDM; 222100),
independent of HLA-DR and HLA-DQ. A genomic polymorphism of LMP7 was
found to be strongly associated with IDDM, and the arg/his-60
polymorphism in LMP2 (309060) was found to be associated with IDDM in
subjects containing an HLA-DR4-DQB1*0302 haplotype.

By genomewide homozygosity mapping followed by candidate gene sequencing
of the 3 patients with autoinflammatory, lipodystrophy, and dermatosis
syndrome (ALDD; 256040) reported by Garg et al. (2010), Agarwal et al.
(2010) identified the same homozygous mutation in the PSMB8 gene (T75M;
177046.0001).

Kitamura et al. (2011) identified a homozygous PSMB8 mutation (G197V;
177046.0002) in 3 Japanese patients from 2 consanguineous families with
the Nakajo-Nishimura autoinflammatory syndrome. One of the families had
previously been reported by Tanaka et al. (1993). The mutation increased
assembly intermediates of immunoproteasomes, resulting in decreased
proteasome function and ubiquitin-coupled protein accumulation in
patient tissues. In addition, IL6 (147620) was highly expressed and
there was reduced expression of PSMB8. In vitro studies showed that
downregulation of PSMB8 inhibited the differentiation of murine and
human adipocytes in vitro, and injection of siRNA against Psmb8 in mouse
skin reduced adipocyte tissue volume. The findings identified PSMB8 as
an essential component and regulator of inflammation and of adipocyte
differentiation, suggesting that immunoproteasomes have pleiotropic
functions in maintaining the homeostasis of a variety of cell types.

In 5 patients with an autoinflammatory disorder previously designated
CANDLE syndrome for 'chronic atypical neutrophilic dermatosis with
lipodystrophy and elevated temperature' (Torrelo et al., 2010), Liu et
al. (2012) identified homozygous mutations in the PSMB8 gene
(177046.0001 and 177046.0004). Two additional patients were heterozygous
for a PSMB8 mutation, but a second pathogenic mutation could not be
found. The patients had high levels of gamma-interferon-induced
protein-10 (CXCL10; 147310), as well as other inflammatory markers.
Microarray profiling suggested dysregulation of the interferon signaling
pathway, particularly gamma-interferon.

ANIMAL MODEL

Fehling et al. (1994) found that mice with a targeted deletion of the
Lmp7 gene had reduced levels of MHC class I cell-surface expression and
presented an endogenous antigen inefficiently.

NOMENCLATURE

The original designation for this gene, RING10, is an acronym for
'really interesting new gene.' The 'D number' of this expressed sequence
was D6S216E.

*FIELD* AV
.0001
AUTOINFLAMMATION, LIPODYSTROPHY, AND DERMATOSIS SYNDROME
PSMB8, THR75MET

In 3 affected members from 2 unrelated families with an autoinflammatory
disorder termed 'joint contractures, muscle atrophy, microcytic anemia,
and panniculitis-induced lipodystrophy' (256040), Agarwal et al. (2010)
identified a homozygous 224C-T transition in exon 2 of the PSMB8 gene,
resulting in a thr75-to-met (T75M) substitution in a highly conserved
residue. The mutation was not found in 275 controls but was present in
heterozygosity in available parents and unaffected sibs. The patients
had previously been reported by Garg et al. (2010) and were of
Portuguese and Mexican origin, respectively. The parents of the
Portuguese patients were consanguineous, whereas consanguinity was
suspected in the parents of the Mexican patients. Haplotype analysis
indicated identity by descent, but the mutation appeared to be ancient.
Molecular dynamics simulation indicated that the mutation relaxed the
protein structure by 1.2 angstrom, and may affect the proteolytic
processing of peptides. Studies of patient lymphocytes showed that the
mutant protein had markedly decreased chymotrypsin-like activity
compared to wildtype, consistent with a decrease in proteasomal activity
and loss of function. Laboratory studies of the 2 Mexican sibs performed
by Agarwal et al. (2010) showed that both had significantly increased
levels of serum IL6 (147620) and gamma-interferon (IFNG; 147570), and 1
had increased IL8 (146930). Other cytokines were not elevated,
suggesting a particular biomarker signature. The disorder is
characterized by childhood onset of joint stiffness and severe
contractures of the hands and feet, erythematous skin lesions with
subsequent development of severe lipodystrophy, and laboratory evidence
of immune dysregulation. Accompanying features include muscle weakness
and atrophy, hepatosplenomegaly, and microcytic anemia. The findings
indicated that dysfunction of the immunoproteasome can result in an
autoinflammatory disease.

Liu et al. (2012) identified a homozygous T75M mutation in 4 unrelated
patients with an autoinflammatory disorder previously designated CANDLE
syndrome for 'chronic atypical neutrophilic dermatosis with
lipodystrophy and elevated temperature' (Torrelo et al., 2010). The
clinical features were similar to those reported by Garg et al. (2010).
Two patients reported by Liu et al. (2012) were of Hispanic origin and 2
were of Spanish origin. However, only 2 patients shared the same
haplotype, suggesting that this is a mutational hotspot. Two additional
patients reported by Liu et al. (2012) were heterozygous for the T75M
mutation, but a second mutation was not detected.

.0002
AUTOINFLAMMATION, LIPODYSTROPHY, AND DERMATOSIS SYNDROME
PSMB8, GLY197VAL

In 3 Japanese patients from 2 consanguineous families with an
autoinflammatory disorder termed 'Nakajo-Nishimura syndrome' (256040),
Kitamura et al. (2011) identified a homozygous G-to-T transversion in
the PSMB8 gene, resulting in a gly197-to-val (G197V) substitution in a
conserved surface-exposed position in a beta-hairpin turn; the affected
residue is G201V in the other isoform of the protein. The mutation was
not found in 624 control alleles. Patient B cells showed decreased
levels of the mature protein and increased proportion of
immunoproteasome intermediates, as well as decreased proteasome
activity, and patient skin cells showed accumulated ubiquitinated
proteins. IL6 (147620) expression was increased in patient tissues. One
of the families had previously been reported by Tanaka et al. (1993).

.0003
AUTOINFLAMMATION, LIPODYSTROPHY, AND DERMATOSIS SYNDROME
PSMB8, GLY201VAL

In 5 unrelated Japanese patients with an autoinflammatory disorder
termed 'Nakajo-Nishimura syndrome' (256040), Arima et al. (2011)
identified a homozygous 602G-T transversion in exon 5 of the PSMB8 gene,
resulting in a gly201-to-val (G201V) substitution in a highly conserved
residue. Haplotype analysis indicated a founder effect. The mutation is
located at the edge of the S8 beta-sheet of the protein, close to the
catalytic residue thr73, and was predicted to cause conformational
changes of catalytic residues thr73 and lys105 as well as affecting the
interface of the protein with other proteasome subunits. Patient-derived
lymphoblastoid cell lines showed markedly decreased chymotrypsin-like
activity compared to controls. Trypsin-like and caspase-like activity
were also decreased. Western blot analysis showed reduced levels of the
20S proteasome, consistent with an assembly defect. Patient cells showed
decreased proteolytic activity with an accumulation of ubiquitinated and
oxidized proteins, and patient skin biopsies showed activation of an
inflammatory response. Patient sera showed increased IL6 (147620) and
IL10 (124092) associated with increased intracellular phosphorylated p38
(MAPK14; 600289), which may be related to increased inflammation. The
findings suggested that decreased proteasome activity can affect signal
transduction and promote inflammation.

.0004
AUTOINFLAMMATION, LIPODYSTROPHY, AND DERMATOSIS SYNDROME
PSMB8, CYS135TER

In a 12.5-year-old Ashkenazi Jewish boy with an autoinflammatory
disorder characterized by chronic atypical neutrophilic dermatosis with
lipodystrophy and elevated temperature (256040), Liu et al. (2012)
identified a homozygous 405C-A transversion in exon 3 of the PSMB8 gene,
resulting in a cys135-to-ter (C135X) substitution, leading to a large
deletion of the terminal 141 residues. The mutant protein was predicted
to interfere with proper assembly of the proteasome. The patient
presented at 1 month of age with fever and skin lesions. He later
developed annular plaques, recurrent fevers, lipodystrophy,
hepatomegaly, arthritis/arthralgia, violaceous eyelids, microcytic
anemia, and elevated liver enzymes.

*FIELD* RF
1. Agarwal, A. K.; Xing, C.; DeMartino, G. N.; Mizrachi, D.; Hernandez,
M. D.; Sousa, A. B.; Martinez de Villarreal, L.; dos Santos, H. G.;
Garg, A.: PSMB8 encoding the beta-5i proteasome subunit is mutated
in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced
lipodystrophy syndrome. Am. J. Hum. Genet. 87: 866-872, 2010.

2. Arima, K.; Kinoshita, A.; Mishima, H.; Kanazawa, N.; Kaneko, T.;
Mizushima, T.; Ichinose, K.; Nakamura, H.; Tsujino, A.; Kawakami,
A.; Matsunaka, M.; Kasagi, S.; and 18 others: Proteasome assembly
defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes
the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc. Nat.
Acad. Sci. 108: 14914-14919, 2011.

3. Deng, G. Y.; Muir, A.; Maclaren, N. K.; She, J.-X.: Association
of LMP2 and LMP7 genes within the major histocompatibility complex
with insulin-dependent diabetes mellitus: population and family studies. Am.
J. Hum. Genet. 56: 528-534, 1995.

4. Fehling, H. J.; Swat, W.; Laplace, C.; Kuhn, R.; Rajewsky, K.;
Muller, U.; von Boehmer, H.: MHC class I expression in mice lacking
the proteasome subunit LMP-7. Science 265: 1234-1237, 1994.

5. Garg, A.; Hernandez, M. D.; Sousa, A. B.; Subramanyam, L.; Martinez
de Villarreal, L.; dos Santos, H. G.; Barboza, O.: An autosomal recessive
syndrome of joint contractures, muscular atrophy, microcytic anemia,
and panniculitis-associated lipodystrophy. J. Clin. Endocr. Metab. 95:
E58-63, 2010. Note: Electronic Article.

6. Glynne, R.; Powis, S. H.; Beck, S.; Kelly, A.; Kerr, L. A.; Trowsdale,
J.: A proteasome-related gene between the two ABC transporter loci
in the class II region of the human MHC. Nature 353: 357-360, 1991.

7. Kitamura, A.; Maekawa, Y.; Uehara, H.; Izumi, K.; Kawachi, I.;
Nishizawa, M.; Toyoshima, Y.; Takahashi, H.; Standley, D. M.; Tanaka,
K.; Hamazaki, J.; Murata, S.; Obara, K.; Toyoshima, I.; Yasutomo,
K.: A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation
and lipodystrophy in humans. J. Clin. Invest. 121: 4150-4160, 2011.

8. Liu, Y.; Ramot, Y.; Torrelo, A.; Paller, A. S.; Si, N.; Babay,
S.; Kim, P. W.; Sheikh, A.; Lee, C.-C. R.; Chen, Y.; Vera, A.; Zhang,
X.; Goldbach-Mansky, R.; Zlotogorski, A.: Mutations in proteasome
subunit beta type 8 cause chronic atypical neutrophilic dermatosis
with lipodystrophy and elevated temperature with evidence of genetic
and phenotypic heterogeneity. Arthritis Rheum. 64: 895-907, 2012.

9. Muchamuel, T.; Basler, M.; Aujay, M. A.; Suzuki, E.; Kalim, K.
W.; Lauer, C.; Sylvain, C.; Ring, E. R.; Shields, J.; Jiang, J.; Shwonek,
P.; Parlati, F.; Demo, S. D.; Bennett, M. K.; Kirk, C. J.; Groettrup,
M.: A selective inhibitor of the immunoproteasome subunit LMP7 blocks
cytokine production and attenuates progression of experimental arthritis. Nature
Med. 15: 781-787, 2009. Note: Erratum: Nature Med. 15: 1333 only,
2009.

10. Tanaka, M.; Miyatani, N.; Yamada, S.; Miyashita, K.; Toyoshima,
I.; Sakuma, K.; Tanaka, K.; Yuasa, T.; Miyatake, T.; Tsubaki, T.:
Hereditary lipo-muscular atrophy with joint contracture, skin eruptions
and hyper-gamma-globulinemia: a new syndrome. Intern. Med. 32: 42-45,
1993.

11. Torrelo, A.; Patel, S.; Colmenero, I.; Gurbindo, D.; Lendinez,
F.; Hernandez, A.; Lopez-Robledillo, J. C.; Dadban, A.; Requena, L.;
Paller, A. S.: Chronic atypical neutrophilic dermatosis with lipodystrophy
and elevated temperature (CANDLE) syndrome. J. Am. Acad. Derm. 62:
489-495, 2010.

12. Witt, E.; Zantopf, D.; Schmidt, M.; Kraft, R.; Kloetzel, P.-M.;
Kruger, E.: Characterisation of the newly identified human Ump1 homologue
POMP and analysis of LMP7(beta-5i) incorporation into 20 S proteasomes. J.
Molec. Biol 301: 1-9, 2000.

*FIELD* CN
Cassandra L. Kniffin - updated: 4/11/2012
Cassandra L. Kniffin - updated: 9/26/2011
Patricia A. Hartz - updated: 4/30/2010
Matthew B. Gross - updated: 9/9/2009
Paul J. Converse - updated: 8/20/2009

*FIELD* CD
Victor A. McKusick: 2/1/1993

*FIELD* ED
carol: 10/10/2012
carol: 4/13/2012
terry: 4/13/2012
ckniffin: 4/11/2012
alopez: 10/24/2011
carol: 9/30/2011
ckniffin: 9/26/2011
wwang: 2/9/2011
ckniffin: 2/7/2011
mgross: 4/30/2010
terry: 4/30/2010
wwang: 12/7/2009
mgross: 9/9/2009
terry: 8/20/2009
mgross: 6/25/2007
carol: 8/16/2001
dkim: 7/23/1998
mark: 6/9/1996
carol: 2/27/1995
carol: 10/18/1993
carol: 2/1/1993

MIM 256040
*RECORD*
*FIELD* NO
256040
*FIELD* TI
#256040 AUTOINFLAMMATION, LIPODYSTROPHY, AND DERMATOSIS SYNDROME; ALDD
;;NAKAJO-NISHIMURA SYNDROME; NKJO;;
read moreJOINT CONTRACTURES, MUSCULAR ATROPHY, MICROCYTIC ANEMIA, AND PANNICULITIS-INDUCED
LIPODYSTROPHY; JMP SYNDROME;;
CHRONIC ATYPICAL NEUTROPHILIC DERMATOSIS WITH LIPODYSTROPHY AND ELEVATED
TEMPERATURE SYNDROME; CANDLE
*FIELD* TX
A number sign (#) is used with this entry because autoinflammation,
lipodystrophy, and dermatosis syndrome (ALDD) can be caused by
homozygous mutation in the PSMB8 gene (177046) on chromosome 6p21.

DESCRIPTION

This autosomal recessive systemic autoinflammatory disorder is
characterized by early childhood onset of annular erythematous plaques
on the face and extremities with subsequent development of partial
lipodystrophy and laboratory evidence of immune dysregulation. More
variable features include recurrent fever, severe joint contractures,
muscle weakness and atrophy, hepatosplenomegaly, basal ganglia
calcifications, and microcytic anemia (summary by Agarwal et al., 2010;
Kitamura et al., 2011; Arima et al., 2011).

This disorder encompasses Nakajo-Nishimura syndrome (NKJO); joint
contractures, muscular atrophy, microcytic anemia, and
panniculitis-induced lipodystrophy (JMP syndrome); and chronic atypical
neutrophilic dermatosis with lipodystrophy and elevated temperature
syndrome (CANDLE). Among Japanese patients, this disorder is best
described as Nakajo-Nishimura syndrome, since both Nakajo (1939) and
Nishimura et al. (1950) contributed to the original phenotypic
descriptions.

CLINICAL FEATURES

Nakajo (1939) described 2 sibs, born of consanguineous parents, with
nodular erythema, elongated and thickened fingers, and emaciation. He
called the disorder 'secondary hypertrophic osteoperiostosis with
pernio.' Both sibs had cardiomegaly and cardiac insufficiency. Nakajo
(1939) thought the changes in the fingers were due to cardiac disease.
Nishimura et al. (1950) reported 3 Japanese patients from 2 families
with hypertrophic pulmonary osteoarthropathy with pernio-like skin
eruptions.

Kitano et al. (1985) found a total of 12 cases including 4 of their own
in the Japanese literature. No cases had been reported in Caucasians at
that time. The 12 cases were distributed in 8 kindreds, most of which
were consanguineous. Other features included large eyes, nose, lips and
ears, disproportionately long and thick fingers, and loss of adipose
tissue in the upper part of the body.

Yamada et al. (1984) and Tanaka et al. (1993) reported a Japanese
brother and sister, born of consanguineous parents, with childhood onset
of systemic joint pain and severe deformities of the fingers as well as
recurrent skin eruptions followed by progressive loss of fat in the
upper and then the lower extremities. The skin eruptions were similar to
erythema nodosum, were associated with fever, and were
steroid-responsive. The patients also had muscle atrophy and weakness in
the areas of lipodystrophy, which resulted in the inability to walk in 1
patient by age 44 years and in the other at age 35 years. Other features
included mild mental retardation, hepatomegaly, macroglossia, and
extensor plantar responses. Laboratory study of the sister at age 44
years showed increased erythrocyte sedimentation rate (ESR),
hypergammaglobulinemia, and impaired glucose tolerance. Brain CT scan
showed calcification of the basal ganglia.

Oyanagi et al. (1987) provided follow-up of the brother reported by
Yamada et al. (1984) who had died of heart failure at age 47 years after
developing cardiac arrhythmias at age 39. Postmortem examination showed
severely atrophic skeletal muscles with fibrosis apparent on microscopic
examination. There were rimmed vacuoles and lobulated fibers. Electron
microscopy showed myofibrillary necrosis, Z-disc streaming, and
intramitochondrial paracrystalline inclusions. These changes were
considered to be indicative of ischemia. Similar, but less severe,
findings were observed in the tongue, extraocular muscles, and heart.
Blood vessels in skeletal muscle showed hyperplasia of the media with
and narrowing and obstruction of the lumen. Small vessels showed
hypertrophy of endothelial cells, whereas arterioles showed hyperplasia
of smooth muscle cells with hypertrophy of endothelial cells and some
degeneration of endothelial cells. The heart was hypertrophic, with
patchy calcification of some vessels. There were also some calcium
deposits in vessels of the basal ganglia. Tanaka et al. (1993) noted
that 13 other Japanese patients with similar clinical manifestations had
been reported, suggesting a distinct clinical entity.

Kitamura et al. (2011) provided clinical details of 3 Japanese patients
with Nakajo syndrome, including the patients reported by Tanaka et al.
(1993). Patients presented with recurrent high fever with nodular
erythema between 1 month and 3 years of age, and began to develop
partial lipodystrophy between 6 and 12 years of age. Lipodystrophy was
particularly prominent in the face, fingers, and upper limbs. Other
features included muscle weakness, deformities of the hands, and
frostbitten hands. Laboratory studies showed increased serum C-reactive
protein, IgG, and IgA, but autoantibodies were not detected.

Arima et al. (2011) reported 7 patients with the disorder, including the
patient reported by Oyanagi et al. (1987). Clinical features included
thin facial appearance, partial lipomuscular atrophy, and long clubbed
fingers. All had a pernio-like, heliotrope-like, or nodular
erythema-like skin rash, and most had periodic fever and joint
contractures. All had evidence of chronic inflammation, as indicated by
elevated ESR and hypergammaglobulinemia. Most had microcytic anemia,
hepatosplenomegaly, and basal ganglia calcification. More variable
features included hyperhidrosis and short stature; only 1 had low IQ.
About half of patients had various autoantibodies.

- JMP Syndrome

Garg et al. (2010) reported a Portuguese man and 2 Mexican sibs with
what they termed JMP syndrome, for joint contractures, muscular atrophy,
microcytic anemia, and panniculitis-induced lipodystrophy. All had
marked generalized lipodystrophy with a progeroid appearance and severe
joint contractures of the elbows, hands, fingers, feet, and toes. Onset
of lipodystrophy appeared in childhood, after appearance of erythematous
nodular skin lesions. Skin biopsy of the skin lesions from 1 patient
showed panniculitis. All patients had short stature and muscle atrophy
and weakness. Other features included dry, stiff skin,
hepatosplenomegaly, microcytic anemia, and hypergammaglobulinemia. Two
had mild hypertriglyceridemia, and all 3 had low HDL cholesterol. The
Mexican sibs both had seizures, but none of the patients had mental
retardation. Garg et al. (2010) noted the phenotypic similarities to the
Japanese patients reported by Tanaka et al. (1993), and postulated an
autoinflammatory disorder. Laboratory studies of the 2 Mexican sibs
performed by Agarwal et al. (2010) showed that both had significantly
increased levels of serum IL6 (147620) and gamma-interferon (IFNG;
147570), and 1 had increased IL8 (146930). Other cytokines were not
elevated, suggesting a particular biomarker signature. Arima et al.
(2011) asserted that the most striking differences between NJKO and JMP
(Garg et al., 2010) were the absence of fever in JMP syndrome and the
absence of seizures in NJKO.

- CANDLE Syndrome

Torrelo et al. (2010) reported 4 patients, including 2 sibs, with an
autoinflammatory disorder characterized by onset in infancy of recurrent
fever, annular erythematous skin lesions, persistent violaceous eyelid
swelling, poor overall growth, partial lipodystrophy, hepatomegaly, and
arthralgias. Laboratory studies showed increased erythrocyte
sedimentation rate, C-reactive protein, and hypochromic anemia. All also
had intermittent elevated liver enzymes. Two patients had
hypertriglyceridemia, 2 had increased platelet counts, and 2 had basal
ganglia calcifications. Histologic analysis of skin lesions showed
atypical mononuclear infiltrates and mature neutrophils. Torrelo et al.
(2010) proposed the acronym chronic atypical neutrophilic dermatosis
with lipodystrophy and elevated temperature syndrome (CANDLE) to refer
to this presumably autosomal recessive disorder. In 3 of the patients
reported by Torrelo et al. (2010), Liu et al. (2012) identified the same
homozygous mutation in the PSMB8 gene (T75M; 177046.0001); the fourth
patient, who had died at age 14 years, was presumed to carry the same
mutation as her sister.

INHERITANCE

The affected sibs reported by Tanaka et al. (1993) were born of
consanguineous parents, indicating an autosomal recessive pattern of
inheritance. Agarwal et al. (2010) confirmed consanguinity of the
parents of the Portuguese patient reported by Garg et al. (2010).

MOLECULAR GENETICS

By genomewide homozygosity mapping followed by candidate gene sequencing
of the 3 patients reported by Garg et al. (2010), Agarwal et al. (2010)
identified the same homozygous mutation in the PSMB8 gene (T75M;
177046.0001). Studies of patient lymphocytes showed that the mutant
protein had markedly decreased chymotrypsin-like activity compared to
wildtype, consistent with a decrease in proteasomal activity and loss of
function. The findings indicated that dysfunction of the
immunoproteasome can result in an autoinflammatory disease.

Kitamura et al. (2011) identified a homozygous PSMB8 mutation (G197V;
177046.0002) in 3 Japanese patients from 2 consanguineous families with
Nakajo syndrome. One of the families had previously been reported by
Tanaka et al. (1993). The mutation increased assembly intermediates of
immunoproteasomes, resulting in decreased proteasome function and
ubiquitin-coupled protein accumulation in patient tissues. In vitro
studies showed that downregulation of PSMB8 inhibited the
differentiation of murine and human adipocytes in vitro, and injection
of siRNA against Psmb8 in mouse skin reduced adipocyte tissue volume.
The findings indicated that PSMB8 has a role in both inflammation and
adipocyte differentiation, explaining the pleiotropic feature of this
disorder.

In 5 unrelated Japanese patients with Nakajo-Nishimura syndrome,
including 1 of the patients originally reported by Yamada et al. (1984),
Arima et al. (2011) identified a homozygous mutation in the PSMB8 gene
(G201V; 177046.0003). Haplotype analysis indicated a founder effect.
Patient-derived lymphoblastoid cell lines showed markedly decreased
chymotrypsin-like, trypsin-like, and caspase-like activity. Arima et al.
(2011) noted that the T75M mutant protein reported by Garg et al. (2010)
caused only diminished chymotrypsin-like activity, whereas other
pepsidase activities remained normal, suggesting a possible biochemical
basis for the slightly different phenotype reported by them (JMP
syndrome).

In 5 patients with CANDLE syndrome, Liu et al. (2012) identified
homozygous mutations in the PSMB8 gene (177046.0001 and 177046.0004).
Three of the patients had previously been reported by Torrelo et al.
(2010). Two additional patients were heterozygous for a PSMB8 mutation,
but a second pathogenic mutation could not be found. The patients had
high levels of gamma-interferon-induced protein-10 (CXCL10; 147310), as
well as other inflammatory markers. Microarray profiling suggested
dysregulation of the interferon signaling pathway, particularly
gamma-interferon.

*FIELD* RF
1. Agarwal, A. K.; Xing, C.; DeMartino, G. N.; Mizrachi, D.; Hernandez,
M. D.; Sousa, A. B.; Martinez de Villarreal, L.; dos Santos, H. G.;
Garg, A.: PSMB8 encoding the beta-5i proteasome subunit is mutated
in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced
lipodystrophy syndrome. Am. J. Hum. Genet. 87: 866-872, 2010.

2. Arima, K.; Kinoshita, A.; Mishima, H.; Kanazawa, N.; Kaneko, T.;
Mizushima, T.; Ichinose, K.; Nakamura, H.; Tsujino, A.; Kawakami,
A.; Matsunaka, M.; Kasagi, S.; and 18 others: Proteasome assembly
defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes
the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc. Nat.
Acad. Sci. 108: 14914-14919, 2011.

3. Garg, A.; Hernandez, M. D.; Sousa, A. B.; Subramanyam, L.; Martinez
de Villarreal, L.; dos Santos, H. G.; Barboza, O.: An autosomal recessive
syndrome of joint contractures, muscular atrophy, microcytic anemia,
and panniculitis-associated lipodystrophy. J. Clin. Endocr. Metab. 95:
E58-63, 2010. Note: Electronic Article.

4. Kitamura, A.; Maekawa, Y.; Uehara, H.; Izumi, K.; Kawachi, I.;
Nishizawa, M.; Toyoshima, Y.; Takahashi, H.; Standley, D. M.; Tanaka,
K.; Hamazaki, J.; Murata, S.; Obara, K.; Toyoshima, I.; Yasutomo,
K.: A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation
and lipodystrophy in humans. J. Clin. Invest. 121: 4150-4160, 2011.

5. Kitano, Y.; Matsunaga, E.; Morimoto, T.; Okada, N.; Sano, S.:
A syndrome with nodular erythema, elongated and thickened fingers,
and emaciation. Arch. Derm. 121: 1053-1056, 1985.

6. Liu, Y.; Ramot, Y.; Torrelo, A.; Paller, A. S.; Si, N.; Babay,
S.; Kim, P. W.; Sheikh, A.; Lee, C.-C. R.; Chen, Y.; Vera, A.; Zhang,
X.; Goldbach-Mansky, R.; Zlotogorski, A.: Mutations in proteasome
subunit beta type 8 cause chronic atypical neutrophilic dermatosis
with lipodystrophy and elevated temperature with evidence of genetic
and phenotypic heterogeneity. Arthritis Rheum. 64: 895-907, 2012.

7. Nakajo, A.: Secondary hypertrophic osteoperiostosis with pernio
(Japanese). J. Derm. Urol. 45: 77-86, 1939.

8. Nishimura, N.; Deki, T.; Kato, S.: Hypertrophic pulmonary osteo-arthropathy
with pernio-like eruption in the two families: eport of the three
cases. (Japanese) Jpn. J. Derm. Venereol. 60: 136-141, 1950.

9. Oyanagi, K.; Sasaki, K.; Ohama, E.; Ikuta, F.; Kawakami, A.; Miyatani,
N.; Miyatake, T.; Yamada, S.: An autopsy case of a syndrome with
muscular atrophy, decreased subcutaneous fat, skin eruption and hyper
gamma-globulinemia: peculiar vascular changes and muscle fiber degeneration. Acta
Neuropath. 73: 313-319, 1987.

10. Tanaka, M.; Miyatani, N.; Yamada, S.; Miyashita, K.; Toyoshima,
I.; Sakuma, K.; Tanaka, K.; Yuasa, T.; Miyatake, T.; Tsubaki, T.:
Hereditary lipo-muscular atrophy with joint contracture, skin eruptions
and hyper-gamma-globulinemia: a new syndrome. Intern. Med. 32: 42-45,
1993.

11. Torrelo, A.; Patel, S.; Colmenero, I.; Gurbindo, D.; Lendinez,
F.; Hernandez, A.; Lopez-Robledillo, J. C.; Dadban, A.; Requena, L.;
Paller, A. S.: Chronic atypical neutrophilic dermatosis with lipodystrophy
and elevated temperature (CANDLE) syndrome. J. Am. Acad. Derm. 62:
489-495, 2010.

12. Yamada, S.; Toyoshima, I.; Mori, S.; Tsubaki, T.: Sibling cases
with lipodystrophic skin change, muscular atrophy, recurrent skin
eruptions, and deformities and contractures of the joints: a possible
new clinical entity. Rinsho Shinkeigaku 24: 703-710, 1984.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Height];
Short stature (less common);
[Other];
Failure to thrive;
Poor growth

HEAD AND NECK:
[Face];
Loss of facial subcutaneous fat;
Periorbital swelling due to violaceous plaques on the eyelids;
[Eyes];
Conjunctivitis;
Episcleritis;
[Mouth];
Macroglossia;
Thick lips

CARDIOVASCULAR:
[Heart];
Cardiac insufficiency (in some);
Arrhythmias (in some)

ABDOMEN:
Prominent abdomen;
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly (variable)

SKELETAL:
Joint contractures;
Narrowing of the joint spaces;
Periarticular osteopenia;
Bone pain;
Joint pain;
[Limbs];
Elbow contractures;
[Hands];
Finger contractures, severe;
Hand contractures, severe;
Clubbed fingers;
Long fingers;
Finger deformities;
Finger swelling;
[Feet];
Toe contractures, severe;
Foot contractures, severe

SKIN, NAILS, HAIR:
[Skin];
Erythematous nodular skin lesions;
Annular erythematous edematous plaques;
Lesions become purpuric;
Residual hyperpigmentation;
Lesions predominantly on face and limbs;
Panniculitis;
Dry, stiff skin;
Frostbitten hands;
HISTOLOGY:;
Mononuclear cell infiltrates;
Atypical mononuclear cells with many mitoses

MUSCLE, SOFT TISSUE:
Lipodystrophy, partial;
Lipodystrophy, generalized, panniculitis-induced (in some);
Marked loss of subcutaneous fat in the limbs, face, and sometimes
chest;
Muscle atrophy (variable);
Muscle weakness

NEUROLOGIC:
[Central nervous system];
Mental retardation, mild (2 families);
Seizures (uncommon);
Basal ganglia calcification

HEMATOLOGY:
Microcytic anemia

IMMUNOLOGY:
Antinuclear autoantibodies (in some)

METABOLIC FEATURES:
Fever, intermittent, recurrent (in some)

LABORATORY ABNORMALITIES:
Increased erythrocyte sedimentation rate;
Hypergammaglobulinemia;
Increased gamma-interferon;
Increased IgG;
Increased IgA;
Increased IL-6;
Increased IL-8;
Increased C-reactive protein;
Abnormal liver enzymes, intermittent;
Increased serum triglycerides

MISCELLANEOUS:
Onset of autoinflammation in infancy or first few years of life;
Onset of lipodystrophy later in childhood;
Onset of joint contractures later in life;
Some features are variable

MOLECULAR BASIS:
Caused by mutation in the proteasome subunit, beta-type, 8 gene (PSMB8,
177046.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 4/11/2012
Cassandra L. Kniffin - revised: 9/26/2011

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 04/25/2012
ckniffin: 4/11/2012
ckniffin: 11/22/2011
joanna: 9/30/2011
ckniffin: 9/26/2011
ckniffin: 2/7/2011

*FIELD* CN
Cassandra L. Kniffin - updated: 4/11/2012
Cassandra L. Kniffin - updated: 9/26/2011

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 04/13/2012
carol: 4/13/2012
terry: 4/13/2012
ckniffin: 4/11/2012
carol: 11/22/2011
ckniffin: 11/22/2011
alopez: 10/24/2011
carol: 9/30/2011
ckniffin: 9/26/2011
carol: 6/17/1994
mimadm: 3/11/1994
carol: 4/1/1992
supermim: 3/17/1992
supermim: 3/20/1990
ddp: 10/27/1989