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FLASH GENE
Symbol CYLD contributors: mct - updated : 08-07-2013
HGNC name cylindromatosis (turban tumor syndrome)
HGNC id 2584
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • three CAP-Gly domains (cytoskeletal-associated-protein-glycine-conserved), which exist in a number of microtubule-binding proteins and are responsible for their association with microtubules
  • a proline rich region
  • an SH3 binding domain
  • a sequence homology to catalytic domain of UCH
  • a C-terminal ubiquitin-specific protease domain, with a small zinc-binding B box domain, truncated at the C-terminus, associated with the hypertrophic skin tumor cylindromatosis
  • mono polymer complex
    HOMOLOGY
    interspecies ortholog to murine Cyld (94.9pc)
    ortholog to chicken CYLD (85pc)
    Homologene
    FAMILY
  • ubiquitin carboxy-terminal hydrolases (UCH) family
  • peptidase C67 family
  • CATEGORY enzyme , tumor suppressor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic,ribosome
    intracellular,cytoplasm,cytoskeleton,microtubule
    text localizes to microtubules in interphase and the midbody during telophase, and its protein levels decrease as cells exit from mitosis
    basic FUNCTION
  • may be involved in ubiquitin-dependent protein catabolism
  • plays an indispensible role in the NF-KB signaling pathway (negatively regulating NFKB1 activation)
  • acting as a negative regulator of TRAF2 and NF-kappa-B signaling pathway,and having receptor-dependent role of in regulating the IkappaB kinase pathway
  • playing a critical role in negatively regulating the c-Jun NH(2)-terminal kinase (JNK)and negatively regulates the activation of MKK7, an upstream kinase known to mediate JNK activation by immune stimuli
  • having a deubiquitinating activity that is directed towards non-Lys-48-linked polyubiquitin chains
  • acting as an ubiquitin thiolesterase
  • acting as a cysteine-type endopeptidase
  • regulates premitotic cell-cycle progression independent of NF-B pathway regulation, and CYLD function is required for efficient mitotic entry
  • having not only tumor-suppressing (apoptosis regulation) but also tumor-promoting activities (enhancer of mitotic entry); this additional function could provide an explanation for the benign nature of most cylindroma lesions
  • acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 AND TRAF7
  • enhancing tubulin polymerization into microtubules by lowering the critical concentration for microtubule assembly
  • having an inhibitory role in regulating type I IFN production during the RARRES3-mediated antiviral response
  • may represent a key regulatory factor in the necroptotic pathway
  • negatively regulates tubulointertitial inflammatory responses via suppressing activation of JNK in tubular epithelial cells, putatively attenuating the progressive tubulointerstitial lesions in IgA nephropathy
  • having role in immunity, lipid metabolism, spermatogenesis, osteoclastogenesis, antimicrobial defense, and inflammation
  • deubiquitinating enzyme that was shown to regulate cell proliferation, cell survival and inflammatory responses, mainly through inhibiting NF-kappaB signalling
  • controls cell growth and division at the G(1)/S-phase as well as cytokinesis by associating with alpha-tubulin and microtubules through its CAP-Gly domains
  • role in promoting inflammatory responses in VSMCs via a mechanism involving MAPK activation but independent of NFKB1 activity, contributing to the pathogenesis of vascular disease
  • in the liver, CYLD acts as an important regulator of hepatocyte homeostasis, protecting cells from spontaneous apoptosis by preventing uncontrolled MAP3K7 and JNK activation
  • essential role of CYLD in maintaining T cell homeostasis as well as normal T regulatory cell function, thereby controlling abnormal T cell responses
  • deubiquitinase specific for lysine63-linked polyubiquitins, highly enriched in the postsynaptic density fraction
  • acts as a key negative regulator to tightly control overactive inflammation
  • role of CYLD as a tumor suppressor in the pathogenesis of in chronic lymphocytic leukemia
  • inhibitor of NFKB-dependent immune responses
  • CELLULAR PROCESS cell cycle
    cell life, cell death/apoptosis
    protein, translation/synthesis
    protein, ubiquitin dependent proteolysis
    PHYSIOLOGICAL PROCESS
    text negative regulation of progression through celle cycle ; ubiquitin cycle
    PATHWAY
    metabolism
    signaling
    apoptosis pathway
    a component
  • structural constituent of ribosome
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • IKBKG (also negatively regulates IkappaB kinase)
  • TRAF2
  • NEMO
  • TRIP
  • PLK1 potential target of CYLD in the regulation of mitotic entry, based on their physical interaction and similar loss-of-function and overexpression phenotypes
  • negative regulator of RARRES3-mediated innate antiviral response
  • interacts with components of the RARRES-3 pathway to inhibit IRF3 signaling and subsequent IFN production
  • IKBKE and CYLD are an oncogene-tumor suppressor network that participates in tumorigenesis (phosphorylation of CYLD at serine 418 decreases its deubiquitinase activity and is necessary for IKBKE-driven)
  • also interacts with HDAC6 in the midbody where it regulates the rate of cytokinesis in a deubiquitinase-independent manner
  • controls epidermal tumorigenesis through blocking the JNK/AP1 signaling pathway at multiple levels
  • is a substrate for CASP8, and caspase 8 cleaves CYLD to generate a survival signal
  • ITCH-CYLD-mediated regulatory mechanism in innate inflammatory cells
  • role for CYLD in tightly regulating the resolution of lung injury and preventing fibrosis by deubiquitinating AKT1
  • CEP192 promotes robust mitotic spindle assembly by regulating K63-polyubiquitin-mediated signaling through CYLD
  • ARHGEF12 is a new substrate of CYLD, providing novel insights into the regulation of RHOA activation
  • PDE4B negatively regulates CYLD via specific activation of MAPK9, but not MAPK8
  • interacted with STAT3 in the cytoplasm and strongly reduced K63-ubiquitination of STAT3 in IL6 stimulated hepatocytes
  • SDC4 interacts with both DDX58 and deubiquitinase CYLD via its C-terminal intracellular region, and likely promotes redistribution of DDX58 and CYLD in a perinuclear pattern post viral infection
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) CYLD , MFT
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral       loss of function
    in pilotrichomas
    tumoral       loss of function
    enhances activation of the transcription factor NF-KB and leads to increased resistance to apoptosis and advanced carcinogenesis
    tumoral   LOH    
    in multiple myeloma with poor prognosis
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    immunologyinfectious 
    transient inhibition of the activity of CYLD by pharmacological agents might provide a strategy to enhance antiviral responses
    ANIMAL & CELL MODELS
  • upon high dose systemic listeriosis infection, all C57BL/6 Cyld(-/-) mice survived, whereas wildtype mice succumbed due to severe liver pathology with impaired pathogen control and hemorrhage within 6 days