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FLASH GENE
Symbol CYLD contributors: mct - updated : 08-07-2013
HGNC name cylindromatosis (turban tumor syndrome)
HGNC id 2584
Corresponding disease
CYLD familial cylindromatosis
MFT multiple familial trichoepithelioma
Location 16q12.1      Physical location : 50.775.960 - 50.835.846
Synonym name
  • cylindromatosis tumor suppressor
  • protein truncated or deleted in cylindromatosis
  • ubiquitin carboxyl-terminal hydrolase
  • deubiquitinating enzyme
  • ubiquitin thiolesterase
  • ubiquitin-specific-processing protease
  • ubiquitin specific peptidase like 2
  • Synonym symbol(s) EAC, CDMT, HSPC057, KIAA0849, CYLD1, CYLDI, USPL2, FLJ20180, FLJ31664, FLJ78684
    EC.number 3.4.19.12
    DNA
    TYPE functioning gene
    STRUCTURE 59.89 kb     20 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    text structure three untranslated exons
    MAPPING cloned Y linked N status provisional
    Physical map
    ABCC11 16q11-q12 ATP-binding cassette, sub-family C (CFTR/MRP), member 11 LONP 16q12.1 peroxisomal lon protease SIAH1 16q12 seven in absentia homolog 1 (Drosophila) LOC255896 16q12.1 similar to molybdenum cofactor synthesis-step 1 protein isoform 2 FLJ31821 16q12.1 hypothetical protein FLJ31821 N4BP1 16q12.1 hypothetical protein FLJ31821 LOC388273 16 LOC388273 CBLN1 16q11.2-q12.2 cerebellin 1 precursor MGC33367 16q12.1 hypothetical protein MGC32905 OAZ 16q12 hypothetical protein MGC32905 ADAM3B 16q12.1 a disintegrin and metalloproteinase domain 3b (cyritestin 2) MRPS21P7 16q12.1 mitochondrial ribosomal protein S21 pseudogene 7 MRPS21P8 16q12.1 mitochondrial ribosomal protein S21 pseudogene 8 FLJ38101 16q12.1 hypothetical protein FLJ38101 FLJ20718 16q12.1 hypothetical protein FLJ20718 LOC390729 16 similar to 60S ribosomal protein L10 (QM protein homolog) TRF4-2 16q12.1 topoisomerase-related function protein 4-2 ADCY7 16q12-q13 adenylate cyclase 7 BRD7 16q12 bromodomain containing 7 NKD1 16q12 naked cuticle homolog 1 (Drosophila) SLIC1 16q12.1 selectin ligand interactor cytoplasmic-1 CARD15 16q12 caspase recruitment domain family, member 15 LOC388274 16 LOC388274 CYLD 16q12-q13 cylindromatosis (turban tumor syndrome) SALL1 16q12.1 sal-like 1 (Drosophila) UNGP1 16q12.1 uracil-DNA glycosylase pseudogene 1 LOC388275 16 similar to Heterogeneous nuclear ribonucleoprotein A1 (Helix-destabilizing protein) (Single-strand binding protein) (hnRNP core protein A1) (HDP-1) (Topoisomerase-inhibitor suppressed) LOC388276 16 LOC388276 LOC388277 16 LOC388277 TNRC9 16q12.2 trinucleotide repeat containing 9 LOC146253 16q12.2 tropomyosin-like LOC390730 16 similar to prohibitin FLJ12178 16q12.2 hypothetical protein FLJ12178
    RNA
    TRANSCRIPTS type messenger
    text alternate untranslated exon 3 and short exon 7 (Bignell 2000)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    20 - 8730 107.3 956 - 2008 18636086
    18 - 8584 107 953 - 2008 18636086
    18 - 8608 107 953 - 2008 18636086
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   moderately
     vessel   highly
    Digestiveliver    
     pancreas exocrine   moderately
    Lymphoid/Immunelymph node   predominantly
    Nervousbrain    
    Reproductivefemale systemovary   
     female systemuterus  moderately
     male systemprostate  highly
     male systemtestis  highly
    Respiratorylung    
     respiratory tractlarynx  highly
    Urinarykidney    
    Visualeyeanterior segmentiris  
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connective   highly
    Lymphoid    
    Muscularstriatumskeletal moderately
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticleukocyte
    cell lineage
    cell lines
    fluid/secretion blood
    at STAGE
    physiological period fetal
    cell cycle     cell cycle, interphase, M
    Text brain, testis, skeletal muscle, eye
    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
  • 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