CYLD_HUMAN
ID CYLD_HUMAN Reviewed; 956 AA.
AC Q9NQC7; O94934; Q7L3N6; Q96EH0; Q9NZX9;
DT 16-AUG-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 193.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase CYLD;
DE EC=3.4.19.12 {ECO:0000269|PubMed:18313383, ECO:0000269|PubMed:27458237, ECO:0000269|PubMed:27591049, ECO:0000269|PubMed:32185393};
DE AltName: Full=Deubiquitinating enzyme CYLD;
DE AltName: Full=Ubiquitin thioesterase CYLD;
DE AltName: Full=Ubiquitin-specific-processing protease CYLD;
GN Name=CYLD {ECO:0000303|PubMed:12917689, ECO:0000312|HGNC:HGNC:2584};
GN Synonyms=CYLD1, KIAA0849 {ECO:0000303|PubMed:10048485}; ORFNames=HSPC057;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND INVOLVEMENT
RP IN FAMILIAL CYLINDROMATOSIS.
RX PubMed=10835629; DOI=10.1038/76006;
RA Bignell G.R., Brown C., Biggs P.J., Lakhani S.R., Jones C., Hansen J.,
RA Blair E., Hofmann B., Siebert R., Turner G., Evans D.G.,
RA Schrander-Stumpel C., Beemer F.A., Van Den Ouweland A., Halley D.,
RA Delpech B., Cleveland M.G., Leigh I., Leisti J., Rasmussen S.,
RA Wallace M.R., Fenske C., Banerjee P., Oiso N., Chaggar R., Merrett S.,
RA Leonard N., Huber M., Hohl D., Chapman P., Burn J., Swift S., Smith A.,
RA Ashworth A., Stratton M.R.;
RT "Identification of the familial cylindromatosis tumor suppressor gene.";
RL Nat. Genet. 25:160-165(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=10048485; DOI=10.1093/dnares/5.6.355;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XII. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 5:355-364(1998).
RN [3]
RP SEQUENCE REVISION.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Uterus;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 397-956.
RC TISSUE=Umbilical cord blood;
RX PubMed=11042152; DOI=10.1101/gr.140200;
RA Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G.,
RA Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W.,
RA Tao J., Huang Q.-H., Zhou J., Hu G.-X., Gu J., Chen S.-J., Chen Z.;
RT "Cloning and functional analysis of cDNAs with open reading frames for 300
RT previously undefined genes expressed in CD34+ hematopoietic stem/progenitor
RT cells.";
RL Genome Res. 10:1546-1560(2000).
RN [6]
RP FUNCTION, INTERACTION WITH IKBKG/NEMO, AND MUTAGENESIS OF CYS-601.
RX PubMed=12917689; DOI=10.1038/nature01803;
RA Trompouki E., Hatzivassiliou E., Tsichritzis T., Farmer H., Ashworth A.,
RA Mosialos G.;
RT "CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB
RT activation by TNFR family members.";
RL Nature 424:793-796(2003).
RN [7]
RP FUNCTION, INTERACTION WITH IKBKG/NEMO, AND MUTAGENESIS OF CYS-601.
RX PubMed=12917690; DOI=10.1038/nature01811;
RA Brummelkamp T.R., Nijman S.M.B., Dirac A.M.G., Bernards R.;
RT "Loss of the cylindromatosis tumour suppressor inhibits apoptosis by
RT activating NF-kappaB.";
RL Nature 424:797-801(2003).
RN [8]
RP FUNCTION, INTERACTION WITH IKBKG/NEMO AND TRAF2, AND MUTAGENESIS OF SER-457
RP AND HIS-871.
RX PubMed=12917691; DOI=10.1038/nature01802;
RA Kovalenko A., Chable-Bessia C., Cantarella G., Israeel A., Wallach D.,
RA Courtois G.;
RT "The tumour suppressor CYLD negatively regulates NF-kappaB signalling by
RT deubiquitination.";
RL Nature 424:801-805(2003).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH TRIP.
RX PubMed=14676304; DOI=10.1084/jem.20031187;
RA Regamey A., Hohl D., Liu J.W., Roger T., Kogerman P., Toftgaard R.,
RA Huber M.;
RT "The tumor suppressor CYLD interacts with TRIP and regulates negatively
RT nuclear factor kappaB activation by tumor necrosis factor.";
RL J. Exp. Med. 198:1959-1964(2003).
RN [10]
RP FUNCTION, INTERACTION WITH TRAF2, ACTIVITY REGULATION, MUTAGENESIS OF
RP SER-418; SER-422; SER-432; SER-436; SER-439; SER-441 AND SER-444, AND
RP PHOSPHORYLATION AT SER-418.
RX PubMed=15870263; DOI=10.1128/mcb.25.10.3886-3895.2005;
RA Reiley W., Zhang M., Wu X., Granger E., Sun S.C.;
RT "Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-
RT dependent phosphorylation.";
RL Mol. Cell. Biol. 25:3886-3895(2005).
RN [11]
RP FUNCTION, MUTAGENESIS OF CYS-601, INTERACTION WITH PLK1, AND SUBCELLULAR
RP LOCATION.
RX PubMed=17495026; DOI=10.1073/pnas.0703268104;
RA Stegmeier F., Sowa M.E., Nalepa G., Gygi S.P., Harper J.W., Elledge S.J.;
RT "The tumor suppressor CYLD regulates entry into mitosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:8869-8874(2007).
RN [12]
RP FUNCTION, SUBUNIT, AND INTERACTION WITH DDX58; MAVS; TBK1 AND IKKE.
RX PubMed=18636086; DOI=10.1038/embor.2008.136;
RA Friedman C.S., O'Donnell M.A., Legarda-Addison D., Ng A., Cardenas W.B.,
RA Yount J.S., Moran T.M., Basler C.F., Komuro A., Horvath C.M., Xavier R.,
RA Ting A.T.;
RT "The tumour suppressor CYLD is a negative regulator of RIG-I-mediated
RT antiviral response.";
RL EMBO Rep. 9:930-936(2008).
RN [13]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=18222923; DOI=10.1074/jbc.m708470200;
RA Gao J., Huo L., Sun X., Liu M., Li D., Dong J.T., Zhou J.;
RT "The tumor suppressor CYLD regulates microtubule dynamics and plays a role
RT in cell migration.";
RL J. Biol. Chem. 283:8802-8809(2008).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [15]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=20194890; DOI=10.1182/blood-2009-10-248526;
RA Gao J., Sun L., Huo L., Liu M., Li D., Zhou J.;
RT "CYLD regulates angiogenesis by mediating vascular endothelial cell
RT migration.";
RL Blood 115:4130-4137(2010).
RN [16]
RP FUNCTION, INTERACTION WITH HDAC6; BCL3 AND MICROTUBULES, AND SUBCELLULAR
RP LOCATION.
RX PubMed=19893491; DOI=10.1038/emboj.2009.317;
RA Wickstrom S.A., Masoumi K.C., Khochbin S., Fassler R., Massoumi R.;
RT "CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and
RT increasing the levels of acetylated tubulin.";
RL EMBO J. 29:131-144(2010).
RN [17]
RP FUNCTION, AND INTERACTION WITH DVL1 AND DVL3.
RX PubMed=20227366; DOI=10.1016/j.molcel.2010.01.035;
RA Tauriello D.V., Haegebarth A., Kuper I., Edelmann M.J., Henraat M.,
RA Canninga-van Dijk M.R., Kessler B.M., Clevers H., Maurice M.M.;
RT "Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling
RT through K63-linked ubiquitination of Dvl.";
RL Mol. Cell 37:607-619(2010).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-418 AND SER-422, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-387, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [20]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH CEP350.
RX PubMed=25134987; DOI=10.1038/ncomms5585;
RA Eguether T., Ermolaeva M.A., Zhao Y., Bonnet M.C., Jain A., Pasparakis M.,
RA Courtois G., Tassin A.M.;
RT "The deubiquitinating enzyme CYLD controls apical docking of basal bodies
RT in ciliated epithelial cells.";
RL Nat. Commun. 5:4585-4585(2014).
RN [21]
RP INVOLVEMENT IN FCYL, AND INVOLVEMENT IN BRSS.
RX PubMed=12190880; DOI=10.1046/j.1523-1747.2002.01839.x;
RA Poblete Gutierrez P., Eggermann T., Hoeller D., Jugert F.K., Beermann T.,
RA Grussendorf-Conen E.-I., Zerres K., Merk H.F., Frank J.;
RT "Phenotype diversity in familial cylindromatosis: a frameshift mutation in
RT the tumor suppressor gene CYLD underlies different tumors of skin
RT appendages.";
RL J. Invest. Dermatol. 119:527-531(2002).
RN [22]
RP INVOLVEMENT IN BRSS.
RX PubMed=12950348; DOI=10.1046/j.1365-2230.2003.01344.x;
RA Scheinfeld N., Hu G., Gill M., Austin C., Celebi J.T.;
RT "Identification of a recurrent mutation in the CYLD gene in Brooke-Spiegler
RT syndrome.";
RL Clin. Exp. Dermatol. 28:539-541(2003).
RN [23]
RP INVOLVEMENT IN MFT1.
RX PubMed=16307661; DOI=10.1111/j.1365-2133.2005.06960.x;
RA Liang Y.H., Gao M., Sun L.D., Liu L.J., Cui Y., Yang S., Fan X., Wang J.,
RA Xiao F.L., Zhang X.J.;
RT "Two novel CYLD gene mutations in Chinese families with trichoepithelioma
RT and a literature review of 16 families with trichoepithelioma reported in
RT China.";
RL Br. J. Dermatol. 153:1213-1215(2005).
RN [24]
RP INVOLVEMENT IN BRSS.
RX PubMed=15854031; DOI=10.1111/j.0022-202x.2005.23688.x;
RA Bowen S., Gill M., Lee D.A., Fisher G., Geronemus R.G., Vazquez M.E.,
RA Celebi J.T.;
RT "Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial
RT cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-
RT phenotype correlation.";
RL J. Invest. Dermatol. 124:919-920(2005).
RN [25]
RP INVOLVEMENT IN FCYL, AND INVOLVEMENT IN MFT1.
RX PubMed=16922728; DOI=10.1111/j.1399-0004.2006.00667.x;
RA Young A.L., Kellermayer R., Szigeti R., Teszas A., Azmi S., Celebi J.T.;
RT "CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and
RT multiple familial trichoepithelioma syndromes.";
RL Clin. Genet. 70:246-249(2006).
RN [26]
RP FUNCTION.
RX PubMed=26670046; DOI=10.1016/j.celrep.2015.11.009;
RA Draber P., Kupka S., Reichert M., Draberova H., Lafont E., de Miguel D.,
RA Spilgies L., Surinova S., Taraborrelli L., Hartwig T., Rieser E.,
RA Martino L., Rittinger K., Walczak H.;
RT "LUBAC-recruited CYLD and A20 regulate gene activation and cell death by
RT exerting opposing effects on linear ubiquitin in signaling complexes.";
RL Cell Rep. 13:2258-2272(2015).
RN [27]
RP INTERACTION WITH SPATA2.
RX PubMed=27307491; DOI=10.15252/embj.201694300;
RA Wagner S.A., Satpathy S., Beli P., Choudhary C.;
RT "SPATA2 links CYLD to the TNF-alpha receptor signaling complex and
RT modulates the receptor signaling outcomes.";
RL EMBO J. 35:1868-1884(2016).
RN [28]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH SPATA2, AND MUTAGENESIS OF
RP CYS-601.
RX PubMed=27458237; DOI=10.15252/embr.201642592;
RA Schlicher L., Wissler M., Preiss F., Brauns-Schubert P., Jakob C.,
RA Dumit V., Borner C., Dengjel J., Maurer U.;
RT "SPATA2 promotes CYLD activity and regulates TNF-induced NF-kappaB
RT signaling and cell death.";
RL EMBO Rep. 17:1485-1497(2016).
RN [29]
RP INTERACTION WITH SPATA2.
RX PubMed=27545878; DOI=10.1016/j.celrep.2016.07.086;
RA Kupka S., De Miguel D., Draber P., Martino L., Surinova S., Rittinger K.,
RA Walczak H.;
RT "SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to
RT Signaling Complexes.";
RL Cell Rep. 16:2271-2280(2016).
RN [30]
RP FUNCTION, AND INTERACTION WITH RNF31.
RX PubMed=26997266; DOI=10.1016/j.celrep.2016.02.062;
RA Hrdinka M., Fiil B.K., Zucca M., Leske D., Bagola K., Yabal M.,
RA Elliott P.R., Damgaard R.B., Komander D., Jost P.J., Gyrd-Hansen M.;
RT "CYLD limits Lys63- and Met1-linked ubiquitin at receptor complexes to
RT regulate innate immune signaling.";
RL Cell Rep. 14:2846-2858(2016).
RN [31]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH SPATA2, AND MUTAGENESIS OF
RP LEU-622.
RX PubMed=27591049; DOI=10.1016/j.molcel.2016.08.001;
RA Elliott P.R., Leske D., Hrdinka M., Bagola K., Fiil B.K., McLaughlin S.H.,
RA Wagstaff J., Volkmar N., Christianson J.C., Kessler B.M., Freund S.M.,
RA Komander D., Gyrd-Hansen M.;
RT "SPATA2 links CYLD to LUBAC, activates CYLD, and controls LUBAC
RT signaling.";
RL Mol. Cell 63:990-1005(2016).
RN [32]
RP FUNCTION, TISSUE SPECIFICITY, AND UBIQUITINATION.
RX PubMed=29291351; DOI=10.1038/nm.4461;
RA Ji Y.X., Huang Z., Yang X., Wang X., Zhao L.P., Wang P.X., Zhang X.J.,
RA Alves-Bezerra M., Cai L., Zhang P., Lu Y.X., Bai L., Gao M.M., Zhao H.,
RA Tian S., Wang Y., Huang Z.X., Zhu X.Y., Zhang Y., Gong J., She Z.G., Li F.,
RA Cohen D.E., Li H.;
RT "The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic
RT steatohepatitis.";
RL Nat. Med. 24:213-223(2018).
RN [33]
RP STRUCTURE BY NMR OF 460-550, AND INTERACTION WITH IKBKG.
RX PubMed=15341735; DOI=10.1016/j.str.2004.07.012;
RA Saito K., Kigawa T., Koshiba S., Sato K., Matsuo Y., Sakamoto A.,
RA Takagi T., Shirouzu M., Yabuki T., Nunokawa E., Seki E., Matsuda T.,
RA Aoki M., Miyata Y., Hirakawa N., Inoue M., Terada T., Nagase T., Kikuno R.,
RA Nakayama M., Ohara O., Tanaka A., Yokoyama S.;
RT "The CAP-Gly domain of CYLD associates with the proline-rich sequence in
RT NEMO/IKKgamma.";
RL Structure 12:1719-1728(2004).
RN [34]
RP STRUCTURE BY NMR OF 125-304.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the 1st and 2nd CAP-Gly domains in human
RT cylindromatosis tumor suppressor CYLD.";
RL Submitted (NOV-2004) to the PDB data bank.
RN [35]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 583-956 IN COMPLEX WITH ZINC IONS,
RP FUNCTION, ACTIVE SITE, MUTAGENESIS OF CYS-601, CATALYTIC ACTIVITY, AND
RP SUBCELLULAR LOCATION.
RX PubMed=18313383; DOI=10.1016/j.molcel.2007.12.018;
RA Komander D., Lord C.J., Scheel H., Swift S., Hofmann K., Ashworth A.,
RA Barford D.;
RT "The structure of the CYLD USP domain explains its specificity for Lys63-
RT linked polyubiquitin and reveals a B box module.";
RL Mol. Cell 29:451-464(2008).
RN [36]
RP VARIANT MFT1 GLY-747, AND VARIANT BRSS GLY-747.
RX PubMed=14632188; DOI=10.1046/j.1523-1747.2003.12514.x;
RA Hu G., Oender M., Gill M., Aksakal B., Oeztas M., Guerer M.A., Celebi J.T.;
RT "A novel missense mutation in CYLD in a family with Brooke-Spiegler
RT syndrome.";
RL J. Invest. Dermatol. 121:732-734(2003).
RN [37]
RP INVOLVEMENT IN FTDALS8, AND VARIANT FTDALS8 VAL-719.
RX PubMed=23338750; DOI=10.1007/s00401-013-1078-9;
RA Dobson-Stone C., Luty A.A., Thompson E.M., Blumbergs P., Brooks W.S.,
RA Short C.L., Field C.D., Panegyres P.K., Hecker J., Solski J.A., Blair I.P.,
RA Fullerton J.M., Halliday G.M., Schofield P.R., Kwok J.B.;
RT "Frontotemporal dementia-amyotrophic lateral sclerosis syndrome locus on
RT chromosome 16p12.1-q12.2: genetic, clinical and neuropathological
RT analysis.";
RL Acta Neuropathol. 125:523-533(2013).
RN [38]
RP VARIANTS FTDALS8 SER-229 AND PHE-615.
RX PubMed=32666117; DOI=10.1093/brain/awaa183;
RA Tabuas-Pereira M., Santana I., Kun-Rodrigues C., Bras J., Guerreiro R.;
RT "CYLD variants in frontotemporal dementia associated with severe memory
RT impairment in a Portuguese cohort.";
RL Brain 143:e67-e67(2020).
RN [39]
RP CHARACTERIZATION OF VARIANT FTDALS8 VAL-719, CHARACTERIZATION OF VARIANT
RP GLY-681, FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH TBK1; OPTN AND
RP SQSTM1, AND SUBCELLULAR LOCATION.
RX PubMed=32185393; DOI=10.1093/brain/awaa039;
RA Dobson-Stone C., Hallupp M., Shahheydari H., Ragagnin A.M.G.,
RA Chatterton Z., Carew-Jones F., Shepherd C.E., Stefen H., Paric E., Fath T.,
RA Thompson E.M., Blumbergs P., Short C.L., Field C.D., Panegyres P.K.,
RA Hecker J., Nicholson G., Shaw A.D., Fullerton J.M., Luty A.A.,
RA Schofield P.R., Brooks W.S., Rajan N., Bennett M.F., Bahlo M.,
RA Landers J.E., Piguet O., Hodges J.R., Halliday G.M., Topp S.D., Smith B.N.,
RA Shaw C.E., McCann E., Fifita J.A., Williams K.L., Atkin J.D., Blair I.P.,
RA Kwok J.B.;
RT "CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral
RT sclerosis.";
RL Brain 143:783-799(2020).
CC -!- FUNCTION: Deubiquitinase that specifically cleaves 'Lys-63'- and linear
CC 'Met-1'-linked polyubiquitin chains and is involved in NF-kappa-B
CC activation and TNF-alpha-induced necroptosis (PubMed:18636086,
CC PubMed:26670046, PubMed:27458237, PubMed:26997266, PubMed:27591049,
CC PubMed:29291351, PubMed:18313383, PubMed:32185393). Negatively
CC regulates NF-kappa-B activation by deubiquitinating upstream signaling
CC factors (PubMed:12917689, PubMed:12917691, PubMed:32185393).
CC Contributes to the regulation of cell survival, proliferation and
CC differentiation via its effects on NF-kappa-B activation
CC (PubMed:12917690). Negative regulator of Wnt signaling
CC (PubMed:20227366). Inhibits HDAC6 and thereby promotes acetylation of
CC alpha-tubulin and stabilization of microtubules (PubMed:19893491).
CC Plays a role in the regulation of microtubule dynamics, and thereby
CC contributes to the regulation of cell proliferation, cell polarization,
CC cell migration, and angiogenesis (PubMed:18222923, PubMed:20194890).
CC Required for normal cell cycle progress and normal cytokinesis
CC (PubMed:17495026, PubMed:19893491). Inhibits nuclear translocation of
CC NF-kappa-B (PubMed:18636086). Plays a role in the regulation of
CC inflammation and the innate immune response, via its effects on NF-
CC kappa-B activation (PubMed:18636086). Dispensable for the maturation of
CC intrathymic natural killer cells, but required for the continued
CC survival of immature natural killer cells (By similarity). Negatively
CC regulates TNFRSF11A signaling and osteoclastogenesis (By similarity).
CC Involved in the regulation of ciliogenesis, allowing ciliary basal
CC bodies to migrate and dock to the plasma membrane; this process does
CC not depend on NF-kappa-B activation (By similarity). Ability to remove
CC linear ('Met-1'-linked) polyubiquitin chains regulates innate immunity
CC and TNF-alpha-induced necroptosis: recruited to the LUBAC complex via
CC interaction with SPATA2 and restricts linear polyubiquitin formation on
CC target proteins (PubMed:26997266, PubMed:26670046, PubMed:27458237,
CC PubMed:27591049). Regulates innate immunity by restricting linear
CC polyubiquitin formation on RIPK2 in response to NOD2 stimulation
CC (PubMed:26997266). Involved in TNF-alpha-induced necroptosis by
CC removing linear ('Met-1'-linked) polyubiquitin chains from RIPK1,
CC thereby regulating the kinase activity of RIPK1 (By similarity).
CC Negatively regulates intestinal inflammation by removing 'Lys-63'
CC linked polyubiquitin chain of NLRP6, thereby reducing the interaction
CC between NLRP6 and PYCARD/ASC and formation of the NLRP6 inflammasome
CC (By similarity). Removes 'Lys-63' linked polyubiquitin chain of MAP3K7,
CC which inhibits phosphorylation and blocks downstream activation of the
CC JNK-p38 kinase cascades (PubMed:29291351).
CC {ECO:0000250|UniProtKB:Q80TQ2, ECO:0000269|PubMed:12917689,
CC ECO:0000269|PubMed:12917690, ECO:0000269|PubMed:12917691,
CC ECO:0000269|PubMed:17495026, ECO:0000269|PubMed:18222923,
CC ECO:0000269|PubMed:18313383, ECO:0000269|PubMed:18636086,
CC ECO:0000269|PubMed:19893491, ECO:0000269|PubMed:20194890,
CC ECO:0000269|PubMed:20227366, ECO:0000269|PubMed:26670046,
CC ECO:0000269|PubMed:26997266, ECO:0000269|PubMed:27458237,
CC ECO:0000269|PubMed:27591049, ECO:0000269|PubMed:29291351,
CC ECO:0000269|PubMed:32185393}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC residue protein attached to proteins as an intracellular targeting
CC signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:18313383,
CC ECO:0000269|PubMed:27458237, ECO:0000269|PubMed:27591049,
CC ECO:0000269|PubMed:32185393};
CC -!- ACTIVITY REGULATION: Inhibited by phosphorylation at serine residues.
CC {ECO:0000269|PubMed:15870263}.
CC -!- SUBUNIT: Interacts (via CAP-Gly domain) with IKBKG/NEMO (via proline-
CC rich C-terminal region) (PubMed:12917689, PubMed:12917690,
CC PubMed:12917691, PubMed:15341735). Interacts with TRAF2 and TRIP
CC (PubMed:12917691, PubMed:14676304). Interacts with PLK1, DVL1, DVL3,
CC MAVS, TBK1, IKKE and DDX58 (PubMed:17495026, PubMed:18636086,
CC PubMed:20227366, PubMed:32185393). Interacts (via CAP-Gly domain) with
CC microtubules (PubMed:19893491). Interacts with HDAC6 and BCL3
CC (PubMed:19893491). Interacts with MAP3K7 (By similarity). Identified in
CC a complex with TRAF6 and SQSTM1 (By similarity). Interacts with OPTN
CC and SQSTM1 (PubMed:32185393). Interacts with CEP350 (PubMed:25134987).
CC Interacts with RNF31; the interaction is indirect and is mediated via
CC SPATA2 (PubMed:26997266). Interacts with SPATA2 (via the PUB domain);
CC the interaction is direct and recruits CYLD to the LUBAC complex,
CC thereby regulating TNF-alpha-induced necroptosis (PubMed:27307491,
CC PubMed:27458237, PubMed:27545878, PubMed:27591049).
CC {ECO:0000250|UniProtKB:Q80TQ2, ECO:0000269|PubMed:12917689,
CC ECO:0000269|PubMed:12917690, ECO:0000269|PubMed:12917691,
CC ECO:0000269|PubMed:14676304, ECO:0000269|PubMed:15341735,
CC ECO:0000269|PubMed:17495026, ECO:0000269|PubMed:18636086,
CC ECO:0000269|PubMed:19893491, ECO:0000269|PubMed:20227366,
CC ECO:0000269|PubMed:25134987, ECO:0000269|PubMed:26997266,
CC ECO:0000269|PubMed:27307491, ECO:0000269|PubMed:27458237,
CC ECO:0000269|PubMed:27545878, ECO:0000269|PubMed:27591049,
CC ECO:0000269|PubMed:32185393}.
CC -!- INTERACTION:
CC Q9NQC7; O95786: DDX58; NbExp=2; IntAct=EBI-2117940, EBI-995350;
CC Q9NQC7; Q9UBN7: HDAC6; NbExp=4; IntAct=EBI-2117940, EBI-301697;
CC Q9NQC7; Q96J02: ITCH; NbExp=3; IntAct=EBI-2117940, EBI-1564678;
CC Q9NQC7; Q96J02-2: ITCH; NbExp=2; IntAct=EBI-2117940, EBI-6672198;
CC Q9NQC7; Q9UM82: SPATA2; NbExp=3; IntAct=EBI-2117940, EBI-744066;
CC Q9NQC7; Q71U36: TUBA1A; NbExp=6; IntAct=EBI-2117940, EBI-302552;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:18313383,
CC ECO:0000269|PubMed:32185393}. Cytoplasm, perinuclear region. Cytoplasm,
CC cytoskeleton. Cell membrane; Peripheral membrane protein; Cytoplasmic
CC side. Cytoplasm, cytoskeleton, microtubule organizing center,
CC centrosome {ECO:0000269|PubMed:25134987}. Cytoplasm, cytoskeleton,
CC spindle {ECO:0000269|PubMed:25134987}. Cytoplasm, cytoskeleton, cilium
CC basal body {ECO:0000250|UniProtKB:Q80TQ2}. Note=Detected at the
CC microtubule cytoskeleton during interphase. Detected at the midbody
CC during telophase. During metaphase, it remains localized to the
CC centrosome but is also present along the spindle (PubMed:25134987).
CC {ECO:0000250|UniProtKB:Q80TQ2, ECO:0000269|PubMed:25134987}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9NQC7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NQC7-2; Sequence=VSP_011277;
CC -!- TISSUE SPECIFICITY: Detected in fetal brain, testis, and skeletal
CC muscle, and at a lower level in adult brain, leukocytes, liver, heart,
CC kidney, spleen, ovary and lung. Isoform 2 is found in all tissues
CC except kidney. {ECO:0000269|PubMed:10835629,
CC ECO:0000269|PubMed:29291351}.
CC -!- PTM: Ubiquitinated. Polyubiquitinated in hepatocytes treated with
CC palmitic acid. Ubiquitination is mediated by E3 ligase TRIM47 and leads
CC to proteasomal degradation. {ECO:0000269|PubMed:29291351}.
CC -!- PTM: Phosphorylated on several serine residues by IKKA and/or IKKB in
CC response to immune stimuli. Phosphorylation requires IKBKG.
CC Phosphorylation abolishes TRAF2 deubiquitination, interferes with the
CC activation of Jun kinases, and strongly reduces CD40-dependent gene
CC activation by NF-kappa-B. {ECO:0000269|PubMed:15870263}.
CC -!- DISEASE: Cylindromatosis, familial (FCYL) [MIM:132700]: A disorder
CC characterized by multiple skin tumors that develop from skin
CC appendages, such as hair follicles and sweat glands. Affected
CC individuals typically develop large numbers of tumors called
CC cylindromas that arise predominantly in hairy parts of the body with
CC approximately 90% on the head and neck. In severely affected
CC individuals, cylindromas may combine into a confluent mass which may
CC ulcerate or become infected (turban tumor syndrome). Individuals with
CC familial cylindromatosis occasionally develop other types of tumors
CC including spiradenomas that begin in sweat glands, and
CC trichoepitheliomas arising from hair follicles.
CC {ECO:0000269|PubMed:12190880, ECO:0000269|PubMed:16922728}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Multiple familial trichoepithelioma 1 (MFT1) [MIM:601606]:
CC Autosomal dominant dermatosis characterized by the presence of many
CC skin tumors predominantly on the face. Since histologic examination
CC shows dermal aggregates of basaloid cells with connection to or
CC differentiation toward hair follicles, this disorder has been thought
CC to represent a benign hamartoma of the pilosebaceous apparatus.
CC Trichoepitheliomas can degenerate into basal cell carcinoma.
CC {ECO:0000269|PubMed:14632188, ECO:0000269|PubMed:16307661,
CC ECO:0000269|PubMed:16922728}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Brooke-Spiegler syndrome (BRSS) [MIM:605041]: An autosomal
CC dominant disorder characterized by the appearance of multiple skin
CC appendage tumors such as cylindroma, trichoepithelioma, and
CC spiradenoma. These tumors are typically located in the head and neck
CC region, appear in early adulthood, and gradually increase in size and
CC number throughout life. {ECO:0000269|PubMed:12190880,
CC ECO:0000269|PubMed:12950348, ECO:0000269|PubMed:14632188,
CC ECO:0000269|PubMed:15854031}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 8
CC (FTDALS8) [MIM:619132]: A neurodegenerative disorder characterized by
CC frontotemporal dementia and/or amyotrophic lateral sclerosis in
CC affected individuals. There is high intrafamilial variation.
CC Frontotemporal dementia is characterized by frontal and temporal lobe
CC atrophy associated with neuronal loss, gliosis, and dementia. Patients
CC exhibit progressive changes in social, behavioral, and/or language
CC function. Amyotrophic lateral sclerosis is characterized by the death
CC of motor neurons in the brain, brainstem, and spinal cord, resulting in
CC fatal paralysis. FTDALS8 is an autosomal dominant form.
CC {ECO:0000269|PubMed:23338750, ECO:0000269|PubMed:32185393,
CC ECO:0000269|PubMed:32666117}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF29029.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=BAA74872.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CYLDID40232ch16q12.html";
CC ---------------------------------------------------------------------------
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DR EMBL; AJ250014; CAB93533.1; -; mRNA.
DR EMBL; AB020656; BAA74872.2; ALT_INIT; mRNA.
DR EMBL; BC012342; AAH12342.1; -; mRNA.
DR EMBL; AF161542; AAF29029.1; ALT_FRAME; mRNA.
DR CCDS; CCDS42164.1; -. [Q9NQC7-2]
DR CCDS; CCDS45482.1; -. [Q9NQC7-1]
DR RefSeq; NP_001035814.1; NM_001042355.1. [Q9NQC7-2]
DR RefSeq; NP_001035877.1; NM_001042412.1. [Q9NQC7-2]
DR RefSeq; NP_056062.1; NM_015247.2. [Q9NQC7-1]
DR RefSeq; XP_005255869.1; XM_005255812.2.
DR RefSeq; XP_006721212.1; XM_006721149.1.
DR RefSeq; XP_011521209.1; XM_011522907.2.
DR RefSeq; XP_016878466.1; XM_017022977.1.
DR RefSeq; XP_016878467.1; XM_017022978.1. [Q9NQC7-2]
DR RefSeq; XP_016878468.1; XM_017022979.1.
DR RefSeq; XP_016878469.1; XM_017022980.1. [Q9NQC7-2]
DR PDB; 1IXD; NMR; -; A=460-550.
DR PDB; 1WHL; NMR; -; A=125-206.
DR PDB; 1WHM; NMR; -; A=228-304.
DR PDB; 2VHF; X-ray; 2.80 A; A/B=583-956.
DR PDB; 7OWD; X-ray; 1.71 A; B=467-552.
DR PDBsum; 1IXD; -.
DR PDBsum; 1WHL; -.
DR PDBsum; 1WHM; -.
DR PDBsum; 2VHF; -.
DR PDBsum; 7OWD; -.
DR AlphaFoldDB; Q9NQC7; -.
DR SMR; Q9NQC7; -.
DR BioGRID; 107920; 840.
DR CORUM; Q9NQC7; -.
DR IntAct; Q9NQC7; 60.
DR MINT; Q9NQC7; -.
DR STRING; 9606.ENSP00000392025; -.
DR BindingDB; Q9NQC7; -.
DR ChEMBL; CHEMBL4630858; -.
DR MEROPS; C67.001; -.
DR iPTMnet; Q9NQC7; -.
DR PhosphoSitePlus; Q9NQC7; -.
DR BioMuta; CYLD; -.
DR DMDM; 51316104; -.
DR EPD; Q9NQC7; -.
DR jPOST; Q9NQC7; -.
DR MassIVE; Q9NQC7; -.
DR MaxQB; Q9NQC7; -.
DR PaxDb; Q9NQC7; -.
DR PeptideAtlas; Q9NQC7; -.
DR PRIDE; Q9NQC7; -.
DR ProteomicsDB; 82139; -. [Q9NQC7-1]
DR ProteomicsDB; 82140; -. [Q9NQC7-2]
DR Antibodypedia; 3193; 325 antibodies from 39 providers.
DR DNASU; 1540; -.
DR Ensembl; ENST00000311559.13; ENSP00000308928.9; ENSG00000083799.18. [Q9NQC7-1]
DR Ensembl; ENST00000398568.6; ENSP00000381574.2; ENSG00000083799.18. [Q9NQC7-2]
DR Ensembl; ENST00000427738.8; ENSP00000392025.3; ENSG00000083799.18. [Q9NQC7-1]
DR Ensembl; ENST00000564326.5; ENSP00000454515.1; ENSG00000083799.18. [Q9NQC7-2]
DR Ensembl; ENST00000569418.5; ENSP00000457576.1; ENSG00000083799.18. [Q9NQC7-2]
DR GeneID; 1540; -.
DR KEGG; hsa:1540; -.
DR MANE-Select; ENST00000427738.8; ENSP00000392025.3; NM_001378743.1; NP_001365672.1.
DR UCSC; uc002egq.2; human. [Q9NQC7-1]
DR CTD; 1540; -.
DR DisGeNET; 1540; -.
DR GeneCards; CYLD; -.
DR GeneReviews; CYLD; -.
DR HGNC; HGNC:2584; CYLD.
DR HPA; ENSG00000083799; Tissue enhanced (bone).
DR MalaCards; CYLD; -.
DR MIM; 132700; phenotype.
DR MIM; 601606; phenotype.
DR MIM; 605018; gene.
DR MIM; 605041; phenotype.
DR MIM; 619132; phenotype.
DR neXtProt; NX_Q9NQC7; -.
DR OpenTargets; ENSG00000083799; -.
DR Orphanet; 211; Familial cylindromatosis.
DR Orphanet; 867; Familial multiple trichoepithelioma.
DR PharmGKB; PA27084; -.
DR VEuPathDB; HostDB:ENSG00000083799; -.
DR eggNOG; KOG3556; Eukaryota.
DR GeneTree; ENSGT00390000018123; -.
DR InParanoid; Q9NQC7; -.
DR OMA; WYIDEAA; -.
DR OrthoDB; 119442at2759; -.
DR PhylomeDB; Q9NQC7; -.
DR TreeFam; TF318734; -.
DR PathwayCommons; Q9NQC7; -.
DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-HSA-5357786; TNFR1-induced proapoptotic signaling.
DR Reactome; R-HSA-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-HSA-5357956; TNFR1-induced NFkappaB signaling pathway.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-936440; Negative regulators of DDX58/IFIH1 signaling.
DR SignaLink; Q9NQC7; -.
DR SIGNOR; Q9NQC7; -.
DR BioGRID-ORCS; 1540; 30 hits in 1131 CRISPR screens.
DR ChiTaRS; CYLD; human.
DR EvolutionaryTrace; Q9NQC7; -.
DR GeneWiki; CYLD_(gene); -.
DR GenomeRNAi; 1540; -.
DR Pharos; Q9NQC7; Tbio.
DR PRO; PR:Q9NQC7; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q9NQC7; protein.
DR Bgee; ENSG00000083799; Expressed in lateral nuclear group of thalamus and 206 other tissues.
DR ExpressionAtlas; Q9NQC7; baseline and differential.
DR Genevisible; Q9NQC7; HS.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0036064; C:ciliary basal body; ISS:UniProtKB.
DR GO; GO:0097542; C:ciliary tip; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0031234; C:extrinsic component of cytoplasmic side of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005874; C:microtubule; IEA:UniProtKB-KW.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005819; C:spindle; IDA:UniProtKB.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0061578; F:Lys63-specific deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0070064; F:proline-rich region binding; IPI:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IDA:UniProtKB.
DR GO; GO:0070266; P:necroptotic process; IBA:GO_Central.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IMP:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:2000493; P:negative regulation of interleukin-18-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0046329; P:negative regulation of JNK cascade; IDA:UniProtKB.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:1901223; P:negative regulation of NIK/NF-kappaB signaling; IDA:UniProtKB.
DR GO; GO:1903753; P:negative regulation of p38MAPK cascade; IDA:UniProtKB.
DR GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
DR GO; GO:0070536; P:protein K63-linked deubiquitination; IDA:UniProtKB.
DR GO; GO:1990108; P:protein linear deubiquitination; IDA:UniProtKB.
DR GO; GO:1902017; P:regulation of cilium assembly; ISS:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; IDA:UniProtKB.
DR GO; GO:2001242; P:regulation of intrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; IMP:UniProtKB.
DR GO; GO:0007346; P:regulation of mitotic cell cycle; IMP:UniProtKB.
DR GO; GO:0060544; P:regulation of necroptotic process; IDA:UniProtKB.
DR GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR Gene3D; 2.30.30.190; -; 3.
DR InterPro; IPR036859; CAP-Gly_dom_sf.
DR InterPro; IPR000938; CAP-Gly_domain.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR001394; Peptidase_C19_UCH.
DR InterPro; IPR018200; USP_CS.
DR InterPro; IPR028889; USP_dom.
DR Pfam; PF01302; CAP_GLY; 2.
DR Pfam; PF00443; UCH; 1.
DR SMART; SM01052; CAP_GLY; 3.
DR SUPFAM; SSF54001; SSF54001; 1.
DR SUPFAM; SSF74924; SSF74924; 3.
DR PROSITE; PS00845; CAP_GLY_1; 1.
DR PROSITE; PS50245; CAP_GLY_2; 2.
DR PROSITE; PS00972; USP_1; 1.
DR PROSITE; PS50235; USP_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Amyotrophic lateral sclerosis;
KW Cell cycle; Cell membrane; Cell projection; Cytoplasm; Cytoskeleton;
KW Disease variant; Hydrolase; Immunity; Innate immunity; Membrane;
KW Metal-binding; Microtubule; Neurodegeneration; Phosphoprotein; Protease;
KW Reference proteome; Repeat; Thiol protease; Tumor suppressor;
KW Ubl conjugation; Ubl conjugation pathway; Wnt signaling pathway; Zinc.
FT CHAIN 1..956
FT /note="Ubiquitin carboxyl-terminal hydrolase CYLD"
FT /id="PRO_0000080698"
FT DOMAIN 153..198
FT /note="CAP-Gly 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00045"
FT DOMAIN 253..286
FT /note="CAP-Gly 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00045"
FT DOMAIN 492..535
FT /note="CAP-Gly 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00045"
FT DOMAIN 592..950
FT /note="USP"
FT REGION 106..593
FT /note="Interaction with TRIP"
FT /evidence="ECO:0000269|PubMed:14676304"
FT REGION 309..353
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 392..411
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 394..469
FT /note="Interaction with TRAF2"
FT REGION 470..554
FT /note="Interaction with IKBKG/NEMO"
FT /evidence="ECO:0000269|PubMed:15341735"
FT REGION 781..833
FT /note="B-box"
FT /evidence="ECO:0000269|PubMed:18313383,
FT ECO:0000269|PubMed:27591049"
FT COMPBIAS 328..353
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 601
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT ECO:0000269|PubMed:18313383"
FT ACT_SITE 871
FT /note="Proton acceptor"
FT /evidence="ECO:0000305|PubMed:18313383"
FT BINDING 788
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:18313383"
FT BINDING 791
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:18313383"
FT BINDING 799
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:18313383"
FT BINDING 802
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:18313383"
FT BINDING 817
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:18313383"
FT BINDING 820
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:18313383"
FT BINDING 825
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:18313383"
FT BINDING 833
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:18313383"
FT MOD_RES 387
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 418
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:15870263,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 422
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 305..307
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10048485,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_011277"
FT VARIANT 229
FT /note="P -> S (in FTDALS8; unknown pathological
FT significance; dbSNP:rs751380834)"
FT /evidence="ECO:0000269|PubMed:32666117"
FT /id="VAR_085113"
FT VARIANT 615
FT /note="S -> F (in FTDALS8; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32666117"
FT /id="VAR_085114"
FT VARIANT 681
FT /note="D -> G (abolished K63-deubiquitinase activity;
FT decreased inhibition of NF-kappa-B; no impact on
FT interaction with TBK1, OPTN and SQSTM)"
FT /evidence="ECO:0000269|PubMed:32185393"
FT /id="VAR_085115"
FT VARIANT 719
FT /note="M -> V (in FTDALS8; increased K63-deubiquitinase
FT activity; increased inhibition of NF-kappa-B; no impact on
FT interaction with TBK1, OPTN and SQSTM)"
FT /evidence="ECO:0000269|PubMed:23338750"
FT /id="VAR_085116"
FT VARIANT 747
FT /note="E -> G (in MFT1 and BRSS; dbSNP:rs121908389)"
FT /evidence="ECO:0000269|PubMed:14632188"
FT /id="VAR_045967"
FT MUTAGEN 418
FT /note="S->A: Reduced phosphorylation; when associated with
FT A-422; A-432 and A-436. Loss of phosphorylation; when
FT associated with A-422; A-432; A-436; A-439; A-441 and A-
FT 444."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 418
FT /note="S->E: Abolishes deubiquitination of TRAF2; when
FT associated with E-422; E-432; E-436; E-439; E-441 and E-
FT 444."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 422
FT /note="S->A: Reduced phosphorylation; when associated with
FT A-418; A-432 and A-436. Loss of phosphorylation; when
FT associated with A-418; A-432; A-436; A-439; A-441 and A-
FT 444."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 422
FT /note="S->E: Abolishes deubiquitination of TRAF2; when
FT associated with E-418; E-432; E-436; E-439; E-441 and E-
FT 444."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 432
FT /note="S->A: Slightly reduced phosphorylation; when
FT associated with A-436. Reduced phosphorylation; when
FT associated with A-418; A-422 and A-436. Loss of
FT phosphorylation; when associated with A-418; A-422; A-436;
FT A-439; A-441 and A-444."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 432
FT /note="S->E: Abolishes deubiquitination of TRAF2; when
FT associated with E-418; E-422; E-436; E-439; E-441 and E-
FT 444."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 436
FT /note="S->A: Slightly reduced phosphorylation; when
FT associated with A-432. Reduced phosphorylation; when
FT associated with A-418; A-422 and A-432. Loss of
FT phosphorylation; when associated with A-418; A-422; A-432;
FT A-439; A-441 and A-444."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 436
FT /note="S->E: Abolishes deubiquitination of TRAF2; when
FT associated with E-418; E-422; E-432; E-439; E-441 and E-
FT 444."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 439
FT /note="S->A: Loss of phosphorylation; when associated with
FT A-418; A-422; A-432; A-436; A-441 and A-444."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 439
FT /note="S->E: Abolishes deubiquitination of TRAF2; when
FT associated with E-418; E-422; E-432; E-436; E-441 and E-
FT 444."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 441
FT /note="S->A: Loss of phosphorylation; when associated with
FT A-418; A-422; A-432; A-436; A-439 and A-444."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 441
FT /note="S->E: Abolishes deubiquitination of TRAF2; when
FT associated with E-418; E-422; E-432; E-436; E-439 and E-
FT 444."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 444
FT /note="S->A: Loss of phosphorylation; when associated with
FT A-418; A-422; A-432; A-436; A-439 and A-441."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 444
FT /note="S->E: Abolishes deubiquitination of TRAF2; when
FT associated with E-418; E-422; E-432; E-436; E-439 and E-
FT 441."
FT /evidence="ECO:0000269|PubMed:15870263"
FT MUTAGEN 457
FT /note="S->A: Abolishes binding to TRAF2."
FT /evidence="ECO:0000269|PubMed:12917691"
FT MUTAGEN 601
FT /note="C->A,S: Loss of deubiquitinating activity."
FT /evidence="ECO:0000269|PubMed:12917689,
FT ECO:0000269|PubMed:12917690, ECO:0000269|PubMed:17495026,
FT ECO:0000269|PubMed:18313383, ECO:0000269|PubMed:27458237"
FT MUTAGEN 622
FT /note="L->D: Impaired interaction with SPATA2."
FT /evidence="ECO:0000269|PubMed:27591049"
FT MUTAGEN 871
FT /note="H->N: Loss of deubiquitinating activity."
FT /evidence="ECO:0000269|PubMed:12917691"
FT STRAND 130..134
FT /evidence="ECO:0007829|PDB:1WHL"
FT STRAND 136..139
FT /evidence="ECO:0007829|PDB:1WHL"
FT STRAND 141..149
FT /evidence="ECO:0007829|PDB:1WHL"
FT STRAND 154..157
FT /evidence="ECO:0007829|PDB:1WHL"
FT STRAND 163..167
FT /evidence="ECO:0007829|PDB:1WHL"
FT STRAND 169..171
FT /evidence="ECO:0007829|PDB:1WHL"
FT TURN 191..193
FT /evidence="ECO:0007829|PDB:1WHL"
FT STRAND 194..197
FT /evidence="ECO:0007829|PDB:1WHL"
FT HELIX 199..201
FT /evidence="ECO:0007829|PDB:1WHL"
FT STRAND 202..204
FT /evidence="ECO:0007829|PDB:1WHL"
FT STRAND 235..240
FT /evidence="ECO:0007829|PDB:1WHM"
FT STRAND 243..253
FT /evidence="ECO:0007829|PDB:1WHM"
FT TURN 259..261
FT /evidence="ECO:0007829|PDB:1WHM"
FT STRAND 264..272
FT /evidence="ECO:0007829|PDB:1WHM"
FT STRAND 278..280
FT /evidence="ECO:0007829|PDB:1WHM"
FT STRAND 283..285
FT /evidence="ECO:0007829|PDB:1WHM"
FT STRAND 293..298
FT /evidence="ECO:0007829|PDB:1WHM"
FT HELIX 299..301
FT /evidence="ECO:0007829|PDB:1WHM"
FT STRAND 302..304
FT /evidence="ECO:0007829|PDB:1WHM"
FT TURN 463..465
FT /evidence="ECO:0007829|PDB:1IXD"
FT STRAND 466..468
FT /evidence="ECO:0007829|PDB:1IXD"
FT STRAND 474..478
FT /evidence="ECO:0007829|PDB:7OWD"
FT STRAND 480..482
FT /evidence="ECO:0007829|PDB:1IXD"
FT STRAND 484..492
FT /evidence="ECO:0007829|PDB:7OWD"
FT STRAND 495..497
FT /evidence="ECO:0007829|PDB:1IXD"
FT STRAND 501..508
FT /evidence="ECO:0007829|PDB:7OWD"
FT STRAND 514..518
FT /evidence="ECO:0007829|PDB:7OWD"
FT STRAND 521..523
FT /evidence="ECO:0007829|PDB:7OWD"
FT STRAND 531..535
FT /evidence="ECO:0007829|PDB:7OWD"
FT HELIX 536..538
FT /evidence="ECO:0007829|PDB:7OWD"
FT STRAND 539..541
FT /evidence="ECO:0007829|PDB:1IXD"
FT TURN 543..547
FT /evidence="ECO:0007829|PDB:7OWD"
FT HELIX 584..586
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 588..591
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 601..611
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 612..614
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 615..617
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 618..622
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 633..642
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 645..650
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 652..654
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 656..669
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 682..690
FT /evidence="ECO:0007829|PDB:2VHF"
FT TURN 691..694
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 699..704
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 710..713
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 730..741
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 743..747
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 750..755
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 760..764
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 773..775
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 778..780
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 781..784
FT /evidence="ECO:0007829|PDB:2VHF"
FT TURN 789..791
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 800..802
FT /evidence="ECO:0007829|PDB:2VHF"
FT TURN 806..811
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 818..824
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 828..830
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 844..846
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 859..868
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 871..877
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 879..881
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 885..889
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 905..908
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 911..914
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 920..925
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 928..930
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 935..940
FT /evidence="ECO:0007829|PDB:2VHF"
FT STRAND 944..948
FT /evidence="ECO:0007829|PDB:2VHF"
FT HELIX 950..952
FT /evidence="ECO:0007829|PDB:2VHF"
SQ SEQUENCE 956 AA; 107316 MW; 01831F9A83424631 CRC64;
MSSGLWSQEK VTSPYWEERI FYLLLQECSV TDKQTQKLLK VPKGSIGQYI QDRSVGHSRI
PSAKGKKNQI GLKILEQPHA VLFVDEKDVV EINEKFTELL LAITNCEERF SLFKNRNRLS
KGLQIDVGCP VKVQLRSGEE KFPGVVRFRG PLLAERTVSG IFFGVELLEE GRGQGFTDGV
YQGKQLFQCD EDCGVFVALD KLELIEDDDT ALESDYAGPG DTMQVELPPL EINSRVSLKV
GETIESGTVI FCDVLPGKES LGYFVGVDMD NPIGNWDGRF DGVQLCSFAC VESTILLHIN
DIIPALSESV TQERRPPKLA FMSRGVGDKG SSSHNKPKAT GSTSDPGNRN RSELFYTLNG
SSVDSQPQSK SKNTWYIDEV AEDPAKSLTE ISTDFDRSSP PLQPPPVNSL TTENRFHSLP
FSLTKMPNTN GSIGHSPLSL SAQSVMEELN TAPVQESPPL AMPPGNSHGL EVGSLAEVKE
NPPFYGVIRW IGQPPGLNEV LAGLELEDEC AGCTDGTFRG TRYFTCALKK ALFVKLKSCR
PDSRFASLQP VSNQIERCNS LAFGGYLSEV VEENTPPKME KEGLEIMIGK KKGIQGHYNS
CYLDSTLFCL FAFSSVLDTV LLRPKEKNDV EYYSETQELL RTEIVNPLRI YGYVCATKIM
KLRKILEKVE AASGFTSEEK DPEEFLNILF HHILRVEPLL KIRSAGQKVQ DCYFYQIFME
KNEKVGVPTI QQLLEWSFIN SNLKFAEAPS CLIIQMPRFG KDFKLFKKIF PSLELNITDL
LEDTPRQCRI CGGLAMYECR ECYDDPDISA GKIKQFCKTC NTQVHLHPKR LNHKYNPVSL
PKDLPDWDWR HGCIPCQNME LFAVLCIETS HYVAFVKYGK DDSAWLFFDS MADRDGGQNG
FNIPQVTPCP EVGEYLKMSL EDLHSLDSRR IQGCARRLLC DAYMCMYQSP TMSLYK
