CYLD Lysine 63 Deubiquitinase
A key tumor suppressor gene regulating NF-κB signaling and cell survival
Gene Information Card
| Symbol | CYLD |
|---|---|
| Full Name | CYLD lysine 63 deubiquitinase |
| Gene Type | Protein-coding |
| Chromosomal Location | 16q12.1 |
| NCBI Gene ID | 1540 ncbi.nlm.nih.gov/gene/1540 |
| Ensembl ID | ENSG00000083799 |
| UniProt ID | Q9NQC7 |
| OMIM ID | 605018 |
| HGNC ID | 2584 |
| Aliases | CYLD1, EAC, MFT, SBS, USPL2, BRSS, CDMT, CYLD2, KIAA0849 |
Description
The CYLD gene encodes a cytoplasmic deubiquitinase that specifically removes lysine-63-linked ubiquitin chains from target proteins, thereby negatively regulating multiple signaling pathways, particularly the NF-κB pathway. CYLD acts as a tumor suppressor, and its loss or mutation is associated with various cancers and inflammatory conditions.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cylindromatosis (turban tumor syndrome) | Germline mutations in CYLD lead to loss of deubiquitinase activity, resulting in constitutive NF-κB activation and uncontrolled cell proliferation in skin appendages. | OMIM #605018; ClinVar |
| Multiple familial trichoepithelioma | Similar to cylindromatosis, mutations in CYLD cause dysregulation of cell growth in hair follicles, leading to benign tumors. | OMIM #601606; ClinVar |
| Brooke-Spiegler syndrome | CYLD mutations cause a spectrum of skin tumors including cylindromas, trichoepitheliomas, and spiradenomas due to impaired ubiquitin editing. | OMIM #605041; ClinVar |
| Multiple myeloma | Somatic deletions or mutations of CYLD are observed in a subset of multiple myeloma cases, contributing to NF-κB activation and tumor progression. | COSMIC; PMID: 20072136 |
| Cutaneous T-cell lymphoma | Loss of CYLD expression has been reported in CTCL, leading to enhanced NF-κB signaling and survival of malignant T cells. | PMID: 21670465 |
| Hepatocellular carcinoma | Reduced CYLD expression is associated with poor prognosis and increased NF-κB activity in HCC. | PMID: 20514449 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 25.4 | Medium |
| Spleen | 20.1 | Medium |
| Lymph node | 18.7 | Medium |
| Bone marrow | 15.3 | Medium |
| Skin | 12.8 | Low |
| Lung | 10.2 | Low |
| Liver | 8.5 | Low |
| Brain | 6.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| K-562 | 18.2 | Chronic myelogenous leukemia cell line |
| HeLa | 15.7 | Cervical adenocarcinoma cell line |
| HepG2 | 12.4 | Hepatocellular carcinoma cell line |
| A549 | 10.8 | Lung carcinoma cell line |
| MCF7 | 9.3 | Breast adenocarcinoma cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1112C>A (p.Ser371*) | Nonsense | Germline (familial cylindromatosis) | Truncated protein lacking catalytic domain, loss of function |
| c.2350C>T (p.Arg784*) | Nonsense | Germline (Brooke-Spiegler syndrome) | Premature stop codon, loss of deubiquitinase activity |
| c.2806C>T (p.Arg936*) | Nonsense | Somatic (multiple myeloma) | Loss of function, NF-κB activation |
| c.2044C>T (p.Arg682Trp) | Missense | Somatic (cutaneous T-cell lymphoma) | Impaired ubiquitin binding, reduced activity |
| c.2272C>T (p.Arg758Cys) | Missense | Somatic (hepatocellular carcinoma) | Altered substrate specificity, loss of tumor suppressor function |
Mutation functional classification
Loss of Function (LOF)
Most CYLD mutations are loss-of-function, leading to reduced or absent deubiquitinase activity. This results in accumulation of ubiquitinated substrates and constitutive activation of NF-κB, promoting cell survival and proliferation.
Gain of Function (GOF)
No gain-of-function mutations have been reported for CYLD; all known pathogenic variants are loss-of-function.
Dominant Negative (DN)
Some missense mutations may exert a dominant-negative effect by dimerizing with wild-type CYLD and impairing its function, though this is not fully established.
View complete mutation data：
Gene Ontology (GO)
| • lysine-63-linked deubiquitinase activity | • cysteine-type endopeptidase activity |
| • protein binding | • zinc ion binding |
| • NF-κB signaling | • negative regulation of NF-κB transcription factor activity |
| • negative regulation of inflammatory response | • cell cycle arrest |
| • apoptotic process | • tumor necrosis factor-mediated signaling pathway |
Pathways
• NF-κB signaling pathway
• TNF signaling pathway
• Toll-like receptor signaling pathway
• RIG-I-like receptor signaling pathway
• NOD-like receptor signaling pathway
• Cytosolic DNA-sensing pathway
Protein Summary
The CYLD protein is a 956-amino-acid deubiquitinase with a catalytic domain at the C-terminus and multiple cytoskeletal-associated protein-glycine-conserved (CAP-Gly) domains at the N-terminus. It specifically cleaves lysine-63-linked polyubiquitin chains from substrates such as TRAF2, TRAF6, and NEMO, thereby inhibiting NF-κB activation. CYLD also regulates microtubule dynamics and cell cycle progression. Its loss leads to increased cell survival and tumorigenesis.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CYLD Knockout HEK293 Cell Line | EDJ-KQ560 | Human | 1540 | Details Get a Quote |
| CYLD Knockout A-549 Cell Line | EDJ-KQ18939 | Human | 1540 | Details Get a Quote |
| CYLD Knockout HCT 116 Cell Line | EDJ-KQ18940 | Human | 1540 | Details Get a Quote |
| CYLD Knockout HeLa Cell Line | EDJ-KQ18941 | Human | 1540 | Details Get a Quote |
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