| Structural highlights
Disease
[CYLD_HUMAN] Defects in CYLD are the cause of familial cylindromatosis (FCYL) [MIM:132700]; also known as Ancell-Spiegler cylindromas or turban tumor syndrome or dermal eccrine cylindromatosis. CYLD is an autosomal dominant and highly tumor type-specific disorder. The tumors (known as cylindromas because of their characteristic microscopic architecture) are believed to arise from or recapitulate the appearance of the eccrine or apocrine cells of the skin that secrete sweat and scent respectively. Cylindromas arise predominantly in hairy parts of the body with approximately 90% on the head and neck. The development of a confluent mass which may ulcerate or become infected has led to the designation 'turban tumor syndrome'. The skin tumors show differentiation in the direction of hair structures, hence the synonym trichoepithelioma.[1] [2] Defects in CYLD are the cause of multiple familial trichoepithelioma type 1 (MFT1) [MIM:601606]; also known as epithelioma adenoides cysticum of Brooke (EAC) or hereditary multiple benign cystic epithelioma or Brooke-Fordyce trichoepitheliomas. MFT1 is an autosomal dominant dermatosis characterized by the presence of many skin tumors predominantly on the face. Since histologic examination shows dermal aggregates of basaloid cells with connection to or differentiation toward hair follicles, this disorder has been thought to represent a benign hamartoma of the pilosebaceous apparatus. Trichoepitheliomas can degenerate into basal cell carcinoma.[3] [4] [5] Defects in CYLD are the cause of Brooke-Spiegler syndrome (BRSS) [MIM:605041]. BRSS is an autosomal dominant disorder characterized by the appearance of multiple skin appendage tumors such as cylindroma, trichoepithelioma, and spiradenoma. These tumors are typically located in the head and neck region, appear in early adulthood, and gradually increase in size and number throughout life.[6] [7] [8] [9]
Function
[CYLD_HUMAN] 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 (By similarity).[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The tumor suppressor CYLD antagonizes NF-kappaB and JNK signaling by disassembly of Lys63-linked ubiquitin chains synthesized in response to cytokine stimulation. Here we describe the crystal structure of the CYLD USP domain, revealing a distinctive architecture that provides molecular insights into its specificity toward Lys63-linked polyubiquitin. We identify regions of the USP domain responsible for this specificity and demonstrate endodeubiquitinase activity toward such chains. Pathogenic truncations of the CYLD C terminus, associated with the hypertrophic skin tumor cylindromatosis, disrupt the USP domain, accounting for loss of CYLD catalytic activity. A small zinc-binding B box domain, similar in structure to other crossbrace Zn-binding folds--including the RING domain found in E3 ubiquitin ligases--is inserted within the globular core of the USP domain. Biochemical and functional characterization of the B box suggests a role as a protein-interaction module that contributes to determining the subcellular localization of CYLD.
The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module.,Komander D, Lord CJ, Scheel H, Swift S, Hofmann K, Ashworth A, Barford D Mol Cell. 2008 Feb 29;29(4):451-64. PMID:18313383[22]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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. PMID:12190880 doi:10.1046/j.1523-1747.2002.01839.x
- ↑ 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. PMID:16922728 doi:10.1111/j.1399-0004.2006.00667.x
- ↑ 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. PMID:16922728 doi:10.1111/j.1399-0004.2006.00667.x
- ↑ 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. PMID:14632188 doi:10.1046/j.1523-1747.2003.12514.x
- ↑ 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. PMID:16307661 doi:10.1111/j.1365-2133.2005.06960.x
- ↑ 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. PMID:12190880 doi:10.1046/j.1523-1747.2002.01839.x
- ↑ 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. PMID:14632188 doi:10.1046/j.1523-1747.2003.12514.x
- ↑ 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. PMID:12950348
- ↑ 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. PMID:15854031 doi:10.1111/j.0022-202X.2005.23688.x
- ↑ 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. PMID:12917689 doi:http://dx.doi.org/10.1038/nature01803
- ↑ 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. PMID:12917690 doi:http://dx.doi.org/10.1038/nature01811
- ↑ 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. PMID:12917691 doi:http://dx.doi.org/10.1038/nature01802
- ↑ 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. PMID:14676304 doi:10.1084/jem.20031187
- ↑ 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. PMID:15870263 doi:10.1128/MCB.25.10.3886-3895.2005
- ↑ 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. PMID:17495026 doi:10.1073/pnas.0703268104
- ↑ 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. PMID:18636086 doi:10.1038/embor.2008.136
- ↑ 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. PMID:18222923 doi:10.1074/jbc.M708470200
- ↑ 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. PMID:20194890 doi:10.1182/blood-2009-10-248526
- ↑ 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. PMID:19893491 doi:10.1038/emboj.2009.317
- ↑ 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. PMID:20227366 doi:10.1016/j.molcel.2010.01.035
- ↑ 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. PMID:18313383 doi:http://dx.doi.org/10.1016/j.molcel.2007.12.018
- ↑ 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. PMID:18313383 doi:http://dx.doi.org/10.1016/j.molcel.2007.12.018
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