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Identification
HMDB Protein ID HMDBP02433
Secondary Accession Numbers
  • 7927
Name Ubiquitin carboxyl-terminal hydrolase CYLD
Synonyms
  1. Deubiquitinating enzyme CYLD
  2. Ubiquitin thiolesterase CYLD
  3. Ubiquitin-specific-processing protease CYLD
Gene Name CYLD
Protein Type Enzyme
Biological Properties
General Function Involved in proline-rich region binding
Specific Function Protease that specifically cleaves 'Lys-63'-linked polyubiquitin chains. Has endodeubiquitinase activity. Plays an important role in the regulation of pathways leading to NF-kappa-B activation. Contributes to the regulation of cell survival, proliferation and differentiation via its effects on NF-kappa-B activation. Negative regulator of Wnt signaling. Inhibits HDAC6 and thereby promotes acetylation of alpha-tubulin and stabilization of microtubules. Plays a role in the regulation of microtubule dynamics, and thereby contributes to the regulation of cell proliferation, cell polarization, cell migration, and angiogenesis. Required for normal cell cycle progress and normal cytokinesis. Inhibits nuclear translocation of NF-kappa-B. Plays a role in the regulation of inflammation and the innate immune response, via its effects on NF-kappa-B activation. Dispensable for the maturation of intrathymic natural killer cells, but required for the continued survival of immature natural killer cells. Negatively regulates TNFRSF11A signaling and osteoclastogenesis
Pathways Not Available
Reactions Not Available
GO Classification
Component
cell part
macromolecular complex
intracellular
ribonucleoprotein complex
ribosome
Function
hydrolase activity, acting on ester bonds
catalytic activity
hydrolase activity
structural molecule activity
ubiquitin thiolesterase activity
structural constituent of ribosome
thiolester hydrolase activity
Process
macromolecule biosynthetic process
cellular macromolecule biosynthetic process
translation
metabolic process
biosynthetic process
catabolic process
macromolecule catabolic process
cellular macromolecule catabolic process
modification-dependent macromolecule catabolic process
modification-dependent protein catabolic process
ubiquitin-dependent protein catabolic process
Cellular Location
  1. Cell membrane
  2. Cytoplasm
  3. Cytoplasm
  4. Cytoplasm
  5. perinuclear region
  6. Peripheral membrane protein
  7. Cytoplasmic side
  8. cytoskeleton
Gene Properties
Chromosome Location Chromosome:1
Locus 16q12.1
SNPs CYLD
Gene Sequence
>2871 bp
ATGAGTTCAGGCTTATGGAGCCAAGAAAAAGTCACTTCACCCTACTGGGAAGAGCGGATT
TTTTACTTGCTTCTTCAAGAATGCAGCGTTACAGACAAACAAACACAAAAGCTCCTTAAA
GTACCGAAGGGAAGTATAGGACAGTATATTCAAGATCGTTCTGTGGGGCATTCAAGGATT
CCTTCTGCAAAAGGCAAGAAAAATCAGATTGGATTAAAAATTCTAGAGCAACCTCATGCA
GTTCTCTTTGTTGATGAAAAGGATGTTGTAGAGATAAATGAAAAGTTCACAGAGTTACTT
TTGGCAATTACCAATTGTGAGGAGAGGTTCAGCCTGTTTAAAAACAGAAACAGACTAAGT
AAAGGCCTCCAAATAGACGTGGGCTGTCCTGTGAAAGTACAGCTGAGATCTGGGGAAGAA
AAATTTCCTGGAGTTGTACGCTTCAGAGGACCCCTGTTAGCAGAGAGGACAGTCTCCGGA
ATATTCTTTGGAGTTGAATTGCTGGAAGAAGGTCGTGGTCAAGGTTTCACTGACGGGGTG
TACCAAGGGAAACAGCTTTTTCAGTGTGATGAAGATTGTGGCGTGTTTGTTGCATTGGAC
AAGCTAGAACTCATAGAAGATGATGACACTGCATTGGAAAGTGATTACGCAGGTCCTGGG
GACACAATGCAGGTCGAACTTCCTCCTTTGGAAATAAACTCCAGAGTTTCTTTGAAGGTT
GGAGAAACAATAGAATCTGGAACAGTTATATTCTGTGATGTTTTGCCAGGAAAAGAAAGC
TTAGGATATTTTGTTGGTGTGGACATGGATAACCCTATTGGCAACTGGGATGGAAGATTT
GATGGAGTGCAGCTTTGTAGTTTTGCGTGTGTTGAAAGTACAATTCTATTGCACATCAAT
GATATCATCCCAGCTTTATCAGAGAGTGTGACGCAGGAAAGGAGGCCTCCCAAACTTGCC
TTTATGTCAAGAGGTGTTGGGGACAAAGGTTCATCCAGTCATAATAAACCAAAGGCTACA
GGATCTACCTCAGACCCTGGAAATAGAAACAGATCTGAATTATTTTATACCTTAAATGGG
TCTTCTGTTGACTCACAACCACAATCCAAATCAAAAAATACATGGTACATTGATGAAGTT
GCAGAAGACCCTGCAAAATCTCTTACAGAGATATCTACAGACTTTGACCGTTCTTCACCA
CCACTCCAGCCTCCTCCTGTGAACTCACTGACCACCGAGAACAGATTCCACTCTTTACCA
TTCAGTCTCACCAAGATGCCCAATACCAATGGAAGTATTGGCCACAGTCCACTTTCTCTG
TCAGCCCAGTCTGTAATGGAAGAGCTAAACACTGCACCCGTCCAAGAGAGTCCACCCTTG
GCCATGCCTCCTGGGAACTCACATGGTCTAGAAGTGGGCTCATTGGCTGAAGTTAAGGAG
AACCCTCCTTTCTATGGGGTAATCCGTTGGATCGGTCAGCCACCAGGACTGAATGAAGTG
CTCGCTGGACTGGAACTGGAAGATGAGTGTGCAGGCTGTACGGATGGAACCTTCAGAGGC
ACTCGGTATTTCACCTGTGCCCTGAAGAAGGCGCTGTTTGTGAAACTGAAGAGCTGCAGG
CCTGACTCTAGGTTTGCATCATTGCAGCCGGTTTCCAATCAGATTGAGCGCTGTAACTCT
TTAGCATTTGGAGGCTACTTAAGTGAAGTAGTAGAAGAAAATACTCCACCAAAAATGGAA
AAAGAAGGCTTGGAGATAATGATTGGGAAGAAGAAAGGCATCCAGGGTCATTACAATTCT
TGTTACTTAGACTCAACCTTATTCTGCTTATTTGCTTTTAGTTCTGTTCTGGACACTGTG
TTACTTAGACCCAAAGAAAAGAACGATGTAGAATATTATAGTGAAACCCAAGAGCTACTG
AGGACAGAAATTGTTAATCCTCTGAGAATATATGGATATGTGTGTGCCACAAAAATTATG
AAACTGAGGAAAATACTTGAAAAGGTGGAGGCTGCATCAGGATTTACCTCTGAAGAAAAA
GATCCTGAGGAATTCTTGAATATTCTGTTTCATCATATTTTAAGGGTAGAACCTTTGCTA
AAAATAAGATCAGCAGGTCAAAAGGTACAAGATTGTTACTTCTATCAAATTTTTATGGAA
AAAAATGAGAAAGTTGGCGTTCCCACAATTCAGCAGTTGTTAGAATGGTCTTTTATCAAC
AGTAACCTGAAATTTGCAGAGGCACCATCATGTCTGATTATTCAGATGCCTCGATTTGGA
AAAGACTTTAAACTATTTAAAAAAATTTTTCCTTCTCTGGAATTAAATATAACAGATTTA
CTTGAAGACACTCCCAGACAGTGCCGGATATGTGGAGGGCTTGCAATGTATGAGTGTAGA
GAATGCTACGACGATCCGGACATCTCAGCTGGAAAAATCAAGCAGTTTTGTAAAACCTGC
AACACTCAAGTCCACCTTCATCCGAAGAGGCTGAATCATAAATATAACCCAGTGTCACTT
CCCAAAGACTTACCCGACTGGGACTGGAGACACGGCTGCATCCCTTGCCAGAATATGGAG
TTATTTGCTGTTCTCTGCATAGAAACAAGCCACTATGTTGCTTTTGTGAAGTATGGGAAG
GACGATTCTGCCTGGCTCTTCTTTGACAGCATGGCCGATCGGGATGGTGGTCAGAATGGC
TTCAACATTCCTCAAGTCACCCCATGCCCAGAAGTAGGAGAGTACTTGAAGATGTCTCTG
GAAGACCTGCATTCCTTGGACTCCAGGAGAATCCAAGGCTGTGCACGAAGACTGCTTTGT
GATGCATATATGTGCATGTACCAGAGTCCAACAATGAGTTTGTACAAATAA
Protein Properties
Number of Residues 956
Molecular Weight 107314.6
Theoretical pI 5.27
Pfam Domain Function
Signals
  • None
Transmembrane Regions
  • None
Protein Sequence
>Ubiquitin carboxyl-terminal hydrolase CYLD
MSSGLWSQEKVTSPYWEERIFYLLLQECSVTDKQTQKLLKVPKGSIGQYIQDRSVGHSRI
PSAKGKKNQIGLKILEQPHAVLFVDEKDVVEINEKFTELLLAITNCEERFSLFKNRNRLS
KGLQIDVGCPVKVQLRSGEEKFPGVVRFRGPLLAERTVSGIFFGVELLEEGRGQGFTDGV
YQGKQLFQCDEDCGVFVALDKLELIEDDDTALESDYAGPGDTMQVELPPLEINSRVSLKV
GETIESGTVIFCDVLPGKESLGYFVGVDMDNPIGNWDGRFDGVQLCSFACVESTILLHIN
DIIPALSESVTQERRPPKLAFMSRGVGDKGSSSHNKPKATGSTSDPGNRNRSELFYTLNG
SSVDSQPQSKSKNTWYIDEVAEDPAKSLTEISTDFDRSSPPLQPPPVNSLTTENRFHSLP
FSLTKMPNTNGSIGHSPLSLSAQSVMEELNTAPVQESPPLAMPPGNSHGLEVGSLAEVKE
NPPFYGVIRWIGQPPGLNEVLAGLELEDECAGCTDGTFRGTRYFTCALKKALFVKLKSCR
PDSRFASLQPVSNQIERCNSLAFGGYLSEVVEENTPPKMEKEGLEIMIGKKKGIQGHYNS
CYLDSTLFCLFAFSSVLDTVLLRPKEKNDVEYYSETQELLRTEIVNPLRIYGYVCATKIM
KLRKILEKVEAASGFTSEEKDPEEFLNILFHHILRVEPLLKIRSAGQKVQDCYFYQIFME
KNEKVGVPTIQQLLEWSFINSNLKFAEAPSCLIIQMPRFGKDFKLFKKIFPSLELNITDL
LEDTPRQCRICGGLAMYECRECYDDPDISAGKIKQFCKTCNTQVHLHPKRLNHKYNPVSL
PKDLPDWDWRHGCIPCQNMELFAVLCIETSHYVAFVKYGKDDSAWLFFDSMADRDGGQNG
FNIPQVTPCPEVGEYLKMSLEDLHSLDSRRIQGCARRLLCDAYMCMYQSPTMSLYK
GenBank ID Protein 14165258
UniProtKB/Swiss-Prot ID Q9NQC7
UniProtKB/Swiss-Prot Entry Name CYLD_HUMAN
PDB IDs
GenBank Gene ID NM_015247.2
GeneCard ID CYLD
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
  1. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  2. Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M: Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell. 2006 Nov 3;127(3):635-48. [PubMed:17081983 ]
  3. Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T: Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones. DNA Res. 2002 Jun 30;9(3):99-106. [PubMed:12168954 ]
  4. Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, Fu G, Shen Y, Fan HY, Lu G, Zhong M, Xu XR, Han ZG, Zhang JW, Tao J, Huang QH, Zhou J, Hu GX, Gu J, Chen SJ, Chen Z: Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells. Genome Res. 2000 Oct;10(10):1546-60. [PubMed:11042152 ]
  5. Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O: Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 1998 Dec 31;5(6):355-64. [PubMed:10048485 ]
  6. Stegmeier F, Sowa ME, Nalepa G, Gygi SP, Harper JW, Elledge SJ: The tumor suppressor CYLD regulates entry into mitosis. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8869-74. Epub 2007 May 10. [PubMed:17495026 ]
  7. Bignell GR, Warren W, Seal S, Takahashi M, Rapley E, Barfoot R, Green H, Brown C, Biggs PJ, Lakhani SR, Jones C, Hansen J, Blair E, Hofmann B, Siebert R, Turner G, Evans DG, Schrander-Stumpel C, Beemer FA, van Den Ouweland A, Halley D, Delpech B, Cleveland MG, Leigh I, Leisti J, Rasmussen S: Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet. 2000 Jun;25(2):160-5. [PubMed:10835629 ]
  8. Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G: CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature. 2003 Aug 14;424(6950):793-6. [PubMed:12917689 ]
  9. Brummelkamp TR, Nijman SM, Dirac AM, Bernards R: Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature. 2003 Aug 14;424(6950):797-801. [PubMed:12917690 ]
  10. Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G: The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature. 2003 Aug 14;424(6950):801-5. [PubMed:12917691 ]
  11. Regamey A, Hohl D, Liu JW, Roger T, Kogerman P, Toftgard R, Huber M: The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor. J Exp Med. 2003 Dec 15;198(12):1959-64. [PubMed:14676304 ]
  12. Reiley W, Zhang M, Wu X, Granger E, Sun SC: Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-dependent phosphorylation. Mol Cell Biol. 2005 May;25(10):3886-95. [PubMed:15870263 ]
  13. Friedman CS, O'Donnell MA, Legarda-Addison D, Ng A, Cardenas WB, Yount JS, Moran TM, Basler CF, Komuro A, Horvath CM, Xavier R, Ting AT: The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO Rep. 2008 Sep;9(9):930-6. doi: 10.1038/embor.2008.136. Epub 2008 Jul 18. [PubMed:18636086 ]
  14. Gao J, Huo L, Sun X, Liu M, Li D, Dong JT, Zhou J: The tumor suppressor CYLD regulates microtubule dynamics and plays a role in cell migration. J Biol Chem. 2008 Apr 4;283(14):8802-9. doi: 10.1074/jbc.M708470200. Epub 2008 Jan 24. [PubMed:18222923 ]
  15. Gao J, Sun L, Huo L, Liu M, Li D, Zhou J: CYLD regulates angiogenesis by mediating vascular endothelial cell migration. Blood. 2010 May 20;115(20):4130-7. doi: 10.1182/blood-2009-10-248526. Epub 2010 Mar 1. [PubMed:20194890 ]
  16. Wickstrom SA, Masoumi KC, Khochbin S, Fassler R, Massoumi R: CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin. EMBO J. 2010 Jan 6;29(1):131-44. doi: 10.1038/emboj.2009.317. Epub 2009 Nov 5. [PubMed:19893491 ]
  17. Tauriello DV, Haegebarth A, Kuper I, Edelmann MJ, Henraat M, Canninga-van Dijk MR, Kessler BM, Clevers H, Maurice MM: Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl. Mol Cell. 2010 Mar 12;37(5):607-19. doi: 10.1016/j.molcel.2010.01.035. [PubMed:20227366 ]
  18. Saito K, Kigawa T, Koshiba S, Sato K, Matsuo Y, Sakamoto A, Takagi T, Shirouzu M, Yabuki T, Nunokawa E, Seki E, Matsuda T, Aoki M, Miyata Y, Hirakawa N, Inoue M, Terada T, Nagase T, Kikuno R, Nakayama M, Ohara O, Tanaka A, Yokoyama S: The CAP-Gly domain of CYLD associates with the proline-rich sequence in NEMO/IKKgamma. Structure. 2004 Sep;12(9):1719-28. [PubMed:15341735 ]
  19. Poblete Gutierrez P, Eggermann T, Holler D, Jugert FK, Beermann T, Grussendorf-Conen EI, Zerres K, Merk HF, Frank J: Phenotype diversity in familial cylindromatosis: a frameshift mutation in the tumor suppressor gene CYLD underlies different tumors of skin appendages. J Invest Dermatol. 2002 Aug;119(2):527-31. [PubMed:12190880 ]
  20. Scheinfeld N, Hu G, Gill M, Austin C, Celebi JT: Identification of a recurrent mutation in the CYLD gene in Brooke-Spiegler syndrome. Clin Exp Dermatol. 2003 Sep;28(5):539-41. [PubMed:12950348 ]
  21. Komander D, Lord CJ, Scheel H, Swift S, Hofmann K, Ashworth A, Barford D: The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module. Mol Cell. 2008 Feb 29;29(4):451-64. doi: 10.1016/j.molcel.2007.12.018. [PubMed:18313383 ]
  22. Hu G, Onder M, Gill M, Aksakal B, Oztas M, Gurer MA, Celebi JT: A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome. J Invest Dermatol. 2003 Oct;121(4):732-4. [PubMed:14632188 ]
  23. Liang YH, Gao M, Sun LD, Liu LJ, Cui Y, Yang S, Fan X, Wang J, Xiao FL, Zhang XJ: Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China. Br J Dermatol. 2005 Dec;153(6):1213-5. [PubMed:16307661 ]
  24. Bowen S, Gill M, Lee DA, Fisher G, Geronemus RG, Vazquez ME, Celebi JT: Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol. 2005 May;124(5):919-20. [PubMed:15854031 ]
  25. Young AL, Kellermayer R, Szigeti R, Teszas A, Azmi S, Celebi JT: CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet. 2006 Sep;70(3):246-9. [PubMed:16922728 ]