ID:CYLD_HUMAN DESCRIPTION: RecName: Full=Ubiquitin carboxyl-terminal hydrolase CYLD; EC=3.4.19.12; AltName: Full=Deubiquitinating enzyme CYLD; AltName: Full=Ubiquitin thioesterase CYLD; AltName: Full=Ubiquitin-specific-processing protease CYLD; 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 (By similarity). CATALYTIC ACTIVITY: Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C- terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal). ENZYME REGULATION: Inhibited by phosphorylation at serine residues. SUBUNIT: Interacts (via CAP-Gly domain) with IKBKG/NEMO (via proline-rich C-terminal region). Interacts with TRAF2 and TRIP. Interacts with PLK1, DVL1, DVL3, MAVS, TBK1, IKKE and DDX58. Interacts (via CAP-Gly domain) with microtubules. Interacts with HDAC6 and BCL3. Interacts with SQSTM1 and MAP3K7. Identified in a complex with TRAF6 and SQSTM1 (By similarity). SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, perinuclear region. Cytoplasm, cytoskeleton. Cell membrane; Peripheral membrane protein; Cytoplasmic side. Note=Detected at the microtubule cytoskeleton during interphase. Detected at the midbody during telophase. TISSUE SPECIFICITY: Detected in fetal brain, testis, and skeletal muscle, and at a lower level in adult brain, leukocytes, liver, heart, kidney, spleen, ovary and lung. Isoform 2 is found in all tissues except kidney. PTM: Phosphorylated on several serine residues by IKKA and/or IKKB in response to immune stimuli. Phosphorylation requires IKBKG. Phosphorylation abolishes TRAF2 deubiquitination, interferes with the activation of Jun kinases, and strongly reduces CD40-dependent gene activation by NF-kappa-B. DISEASE: 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. DISEASE: 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. DISEASE: 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. SIMILARITY: Belongs to the peptidase C67 family. SIMILARITY: Contains 3 CAP-Gly domains. SEQUENCE CAUTION: Sequence=AAF29029.1; Type=Frameshift; Positions=776, 808, 932; Sequence=BAA74872.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q9NQC7
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0004843 thiol-dependent ubiquitin-specific protease activity GO:0005515 protein binding GO:0008233 peptidase activity GO:0008234 cysteine-type peptidase activity GO:0008270 zinc ion binding GO:0016787 hydrolase activity GO:0019901 protein kinase binding GO:0036459 thiol-dependent ubiquitinyl hydrolase activity GO:0046872 metal ion binding GO:0061578 Lys63-specific deubiquitinase activity GO:0070064 proline-rich region binding GO:1990380 Lys48-specific deubiquitinase activity GO:0003735 structural constituent of ribosome
Biological Process: GO:0002376 immune system process GO:0006508 proteolysis GO:0006511 ubiquitin-dependent protein catabolic process GO:0007049 cell cycle GO:0007346 regulation of mitotic cell cycle GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway GO:0016055 Wnt signaling pathway GO:0016579 protein deubiquitination GO:0032088 negative regulation of NF-kappaB transcription factor activity GO:0032480 negative regulation of type I interferon production GO:0043369 CD4-positive or CD8-positive, alpha-beta T cell lineage commitment GO:0043393 regulation of protein binding GO:0045087 innate immune response GO:0045577 regulation of B cell differentiation GO:0045581 negative regulation of T cell differentiation GO:0045582 positive regulation of T cell differentiation GO:0048872 homeostasis of number of cells GO:0050862 positive regulation of T cell receptor signaling pathway GO:0070266 necroptotic process GO:0070423 nucleotide-binding oligomerization domain containing signaling pathway GO:0070507 regulation of microtubule cytoskeleton organization GO:0070536 protein K63-linked deubiquitination GO:0071108 protein K48-linked deubiquitination GO:0090090 negative regulation of canonical Wnt signaling pathway GO:1901026 ripoptosome assembly involved in necroptotic process GO:1901223 negative regulation of NIK/NF-kappaB signaling GO:1902017 regulation of cilium assembly GO:1903829 positive regulation of cellular protein localization GO:1990108 protein linear deubiquitination GO:2001238 positive regulation of extrinsic apoptotic signaling pathway GO:2001242 regulation of intrinsic apoptotic signaling pathway GO:0002181 cytoplasmic translation
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Common Gene Haplotype Alleles 
