Function
Deubiquitinase that specifically cleaves 'Lys-63'- and linear 'Met-1'-linked polyubiquitin chains and is involved in NF-kappa-B activation and TNF-alpha-induced necroptosis. Negatively regulates NF-kappa-B activation by deubiquitinating upstream signaling factors. 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. Involved in the regulation of ciliogenesis, allowing ciliary basal bodies to migrate and dock to the plasma membrane; this process does not depend on NF-kappa-B activation. Ability to remove linear ('Met-1'-linked) polyubiquitin chains regulates innate immunity and TNF-alpha-induced necroptosis: recruited to the LUBAC complex via interaction with SPATA2 and restricts linear polyubiquitin formation on target proteins. Regulates innate immunity by restricting linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation. Involved in TNF-alpha-induced necroptosis by removing linear ('Met-1'-linked) polyubiquitin chains from RIPK1, thereby regulating the kinase activity of RIPK1. Removes 'Lys-63' linked polyubiquitin chain of MAP3K7, which inhibits phosphorylation and blocks downstream activation of the JNK-p38 kinase cascades.
Gene References into Functions
- A substantial number of CLL patient samples express sCYLD. PMID: 28566736
- No genotype-phenotype correlation was found in tumor disorders of the skin appendages associated with mutations in the CYLD gene. PMID: 29974194
- Catalytic domain mutation in CYLD gene is associated with osteosarcoma. PMID: 29807073
- Studied the role of maternally expressed 3 (lncRNA-MEG3) as an antitumor lncRNA for malignant melanoma by regulating miR-499-5p/CYLD axis. PMID: 29808164
- CYLD inhibits post-transcriptional regulation of RIG-I and MDA5 expression following TLR3 activation in MCs. CYLD may be involved in the pathogenesis of CKD PMID: 29166644
- miR-197-3p-induced downregulation of CYLD promotes cell proliferation and inhibits cell apoptosis in lung adenocarcinoma cell lines. PMID: 29286108
- Knockdown of CYLD expression reversed the cell proliferation promotion by miR1288in in glioblastoma. PMID: 28901464
- TNF phase III signalling displays ongoing TNFR1/NF-kappa B activation in monocytic cells. High- and low-sensitive genes are induced including differentially regulated A20. A20 strictly controls this signalling in an IKK- and partially RIP-dependent manner. The A20-mediated control mechanisms are supported by ABIN1 and CYLD. PMID: 28629782
- Low expression of CYLD is associated with glioma. PMID: 28534976
- theses data show that CYLD regulates the magnitude of ubiquitination of several major effectors of the EGFR pathway by assisting the recruitment of the ubiquitin ligase Cbl-b to the activated EGFR complex. PMID: 28572092
- Through deceasing the expression of Cylindromatosis (CYLD), a K63-specific DUB and endogenous blocker of NF-kappaB signaling, miR-130b can in return sustain the persistent activation of NF-kappaB, which may promote the malignant progression of transitional cell carcinoma of bladder. PMID: 27391066
- While previous reports have described CYLD as a regulator of DVL proteins; this data suggests the presence of a more complicated reciprocal regulatory mechanism in CML cell lines. PMID: 28840581
- Thrombin-mediated MALT1 protease activation triggers acute disruption of endothelial barrier integrity via CYLD cleavage. PMID: 27681433
- MiR-767 acted as a role of tumor promoter by targeting CYLD in human melanoma. PMID: 29054757
- SPATA2 has been described as a previously unrecognized factor in the linear ubiquitin chain assembly complex-dependent signaling pathways that serves as an adaptor between HOIP and CYLD, thereby enabling recruitment of CYLD to signaling complexes. PMID: 27545878
- The data reveal SPATA2 as a high-affinity binding partner of CYLD and HOIP, and a regulatory component of linear ubiquitin chain assembly complex-mediated NF-kappaB signaling. PMID: 27591049
- The current investigations identified a subset of HPV-positive HNSCCs with mutations in the genes TRAF3 (tumor necrosis factor receptor-associated factor 3) and CYLD (cylindromatosis lysine 63 deubiquitinase). Defects in TRAF3 and CYLD correlated with the activation of transcriptional factor nuclear factor kappaB, episomal HPV status of tumors, and improved patient survival. PMID: 28295222
- The predicted PUB domain in the N-terminus of SPATA2 interacts with the USP domain of CYLD and SPATA2 is required for recruitment of CYLD to the TNF-alpha receptor-associated signaling complexes. PMID: 27307491
- STAT3 and miR-181b control each other's expression in a positive feedback loop that regulates SFCs via CYLD pathway. PMID: 27189061
- CYLD Promotes TNF-alpha-Induced Cell Necrosis Mediated by RIP-1 in Human Lung Cancer Cells PMID: 27738385
- Low CYLD expression is associated with hepatocellular carcinoma. PMID: 28184924
- miR20a directly repressed the expression of CYLD, leading to activation of the NFkappaB pathway and the downstream targets, livin and survivin, which potentially induced GC chemoresistance. PMID: 27357419
- Data show that cylindromatosis (CYLD) overexpression and livin knockdown might improve gemcitabine chemosensitivity by decreasing autophagy and increasing apoptosis in bladder cancer (BCa) cells. PMID: 27448305
- aberrantly expressed miR-130b may regulate cell apoptosis and proliferation of human gastric cancer cells via CYLD, which appears to be a promising therapeutic target for gastric cancer PMID: 26711782
- These results demonstrate the involvement of histone deacetylases in the down regulation of Cyld expression in hepatocellular carcinoma cells. PMID: 27570065
- Novel CYLD germline mutations c.1821_1826+1delinsCT/L607Ffs*9, c.2666A>T/p.D889V and c.2712delT/p.905Kfs*8 were identified in unrelated Brooke-Spiegler Syndrome patients. PMID: 26329847
- Study founds the levels of CYLD and SMAD7 significantly decreased in oral squamous cell carcinoma (OSSC) cells and proposes a model that CYLD suppresses OSCC metastases through SMAD7. Downregulation of CYLD appears to directly contribute to the distal metastases of primary OSCC and subsequently poor prognosis. PMID: 26982322
- Haplotype analysis was performed for the patients with multiple familial trichoepithelioma type 1, patients with familial cylindromatosis and a patient with Brooke-Spiegler syndrome, all of whom carry the same heterozygous nonsense CYLD mutation. PMID: 26861065
- Ultraviolet radiation induced CYLD translocation from the cytoplasm to microtubules, posttranslational modification and degradation in a proteasome-independent manner. PMID: 26717101
- Deubiquitinase CYLD negatively regulates MyD88-mediated signaling by directly interacting with MyD88 and deubiquitinating nontypeable Haemophilus influenzae (NTHi)-induced K63-linked polyubiquitination of MyD88 at lysine 231. PMID: 26719415
- CYLD interrupts the ERK- and p38-/AP-1 and c-Myc pathways to suppress Nrf2-operated antioxidative capacity, thereby enhancing oxidative stress in the heart. PMID: 25935309
- Data suggest OPTN (optineurin) is involved in up-regulation of innate immunity in mitosis; mechanism involves phosphorylation/nuclear translocation of CYLD and phosphorylation/mitochondrial translocation of TBK1 (NF-kB-activating kinase). PMID: 25923723
- CaMKII-mediated recruitment and upregulation of CYLD is expected to remove K63-linked polyubiquitins and facilitate proteasomal degradation at the postsynaptic density. PMID: 24614225
- The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells. PMID: 25134987
- Phenotype-genotype correlations for clinical variants caused by CYLD mutations. [Review] PMID: 25782638
- we identified a novel mutation of the CYLD gene in a Chinese multiple familial trichoepithelioma family. PMID: 25117167
- Low CYLD expression is associated with colorectal cancer. PMID: 25824771
- Expression of nuclear CYLD is a novel prognostic factor for improved survival in patients with HCC undergoing liver resection or transplantation. PMID: 25329885
- A recurrent R936X nonsense mutation of CYLD was identified in a large Chinese family with multiple familial trichoepithelioma. PMID: 25751345
- Clinical management of patients with germline CYLD mutations is challenging and we discuss genetic counselling and surgical interventions PMID: 26370355
- Data show that inhibiting the expression of cylindromatosis (CYLD) gene can suppress the proliferation and migration of umbilical vein endothelial cells (HUVECs). PMID: 26271973
- TRAF-6 mediates S. p-induced PAI-1 expression, and CYLD inhibits PAI-1 expression probably through deubiquitinating TRAF-6 PMID: 26056944
- DC-SIGN directs adaptive T helper cell type-2immunity to fucose-expressing pathogens via an IKKepsilon-CYLD-dependent signalling pathway leading to Bcl3 activation. PMID: 24867235
- Here, we report a novel interaction between CYLD and MIB2 that supports the hypothesis that the CYLD/MIB2 interaction might play a pathogenic role in human cancer. PMID: 25565632
- A heterozygous missense mutation (c.1112C>A) in the 9th exon of the CYLD gene was detected in some mother-daughter patients with multiple trichoepitheliomas. PMID: 25501176
- CYLD displayed its ability to restrict the cells in G2 phase of cell cycle PMID: 25641919
- the 35kDa CYLD cleaved factor generated by MALT-1 mediated proteolytic cleavage was conspicuously present in human T- ALL subjects of pediatric age group. PMID: 25130432
- CYLD negatively regulates nontypeable Haemophilus influenzae-induced IL-8 expression via MKP-1-dependent inhibition of ERK. PMID: 25389768
- Overexpression of non-SUMOylatable mutant CYLD in neuroblastoma cells reduced retinoic acid-induced NF-kappaB activation and differentiation of cells, but instead promoted cell death. PMID: 24909169
- Report a novel heterozygous frameshift mutation c.1169_1170delCA (p.Thr390Argfs) of the CYLD gene in Chinese family with multiple familial trichoepithelioma. PMID: 25234269
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Involvement in disease
Cylindromatosis, familial (FCYL); Multiple familial trichoepithelioma 1 (MFT1); Brooke-Spiegler syndrome (BRSS)
Subcellular Location
Cytoplasm. Cytoplasm, perinuclear region. Cytoplasm, cytoskeleton. Cell membrane; Peripheral membrane protein; Cytoplasmic side. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome. Cytoplasm, cytoskeleton, spindle. Cytoplasm, cytoskeleton, cilium basal body.
Protein Families
Peptidase C19 family
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.
