CYLD

CYLD (CYLD Lysine 63 Deubiquitinase) is a Protein Coding gene. Diseases associated with CYLD include Cylindromatosis, Familial and Brooke-Spiegler Syndrome. Among its related pathways are Metabolism of proteins and Innate Immune System. Gene Ontology (GO) annotations related to this gene include protein kinase binding and thiol-dependent ubiquitin-specific protease activity.

CYLD Lysine 63 Deubiquitinase

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 (PubMed:18636086, PubMed:26670046, PubMed:27458237, PubMed:26997266, PubMed:27591049, PubMed:29291351, PubMed:18313383).

Plays an important role in the regulation of pathways leading to NF-kappa-B activation (PubMed:12917689, PubMed:12917691).

Contributes to the regulation of cell survival, proliferation and differentiation via its effects on NF-kappa-B activation (PubMed:12917690).

Negative regulator of Wnt signaling (PubMed:20227366).

Inhibits HDAC6 and thereby promotes acetylation of alpha-tubulin and stabilization of microtubules (PubMed:19893491).

Plays a role in the regulation of microtubule dynamics, and thereby contributes to the regulation of cell proliferation, cell polarization, cell migration, and angiogenesis (PubMed:18222923, PubMed:20194890).

Required for normal cell cycle progress and normal cytokinesis (PubMed:17495026, PubMed:19893491).

Inhibits nuclear translocation of NF-kappa-B (PubMed:18636086).

Plays a role in the regulation of inflammation and the innate immune response, via its effects on NF-kappa-B activation (PubMed:18636086).

Dispensable for the maturation of intrathymic natural killer cells, but required for the continued survival of immature natural killer cells (By similarity).

Negatively regulates TNFRSF11A signaling and osteoclastogenesis (By similarity).

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 (By similarity).

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 (PubMed:26997266, PubMed:26670046, PubMed:27458237, PubMed:27591049).

Regulates innate immunity by restricting linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation (PubMed:26997266).

Involved in TNF-alpha-induced necroptosis by removing linear ('Met-1'-linked) polyubiquitin chains from RIPK1, thereby regulating the kinase activity of RIPK1 (By similarity).

Removes 'Lys-63' linked polyubiquitin chain of MAP3K7, which inhibits phosphorylation and blocks downstream activation of the JNK-p38 kinase cascades (PubMed:29291351).

Cell cycle Source: UniProtKB-KW
Innate immune response Source: UniProtKB
Necroptotic process Source: GO_Central
Negative regulation of canonical Wnt signaling pathway Source: UniProtKB
Negative regulation of JNK cascade Source: UniProtKB
Negative regulation of NF-kappaB transcription factor activity Source: UniProtKB
Negative regulation of NIK/NF-kappaB signaling Source: UniProtKB
Negative regulation of p38MAPK cascade Source: UniProtKB
Negative regulation of type I interferon production Source: Reactome
Nucleotide-binding oligomerization domain containing signaling pathway Source: Reactome
Positive regulation of extrinsic apoptotic signaling pathway Source: UniProtKB
Protein deubiquitination Source: UniProtKB
Protein K63-linked deubiquitination Source: UniProtKB
Protein linear deubiquitination Source: UniProtKB
Regulation of cilium assembly Source: UniProtKB
Regulation of inflammatory response Source: UniProtKB
Regulation of intrinsic apoptotic signaling pathway Source: UniProtKB
Regulation of microtubule cytoskeleton organization Source: UniProtKB
Regulation of mitotic cell cycle Source: UniProtKB
Regulation of necroptotic process Source: UniProtKB
Regulation of tumor necrosis factor-mediated signaling pathway Source: UniProtKB
Ubiquitin-dependent protein catabolic process Source: InterPro
Wnt signaling pathway Source: UniProtKB-KW

Cell membrane; Cytoskeleton; Centrosome; Spindle; Cilium basal body; Cytoplasm; Perinuclear region. Detected at the microtubule cytoskeleton during interphase. Detected at the midbody during telophase. During metaphase, it remains localized to the centrosome but is also present along the spindle (PubMed:25134987).

Cylindromatosis, familial (FCYL):
A disorder characterized by multiple skin tumors that develop from skin appendages, such as hair follicles and sweat glands. Affected individuals typically develop large numbers of tumors called cylindromas that arise predominantly in hairy parts of the body with approximately 90% on the head and neck. In severely affected individuals, cylindromas may combine into a confluent mass which may ulcerate or become infected (turban tumor syndrome). Individuals with familial cylindromatosis occasionally develop other types of tumors including spiradenomas that begin in sweat glands, and trichoepitheliomas arising from hair follicles.
Multiple familial trichoepithelioma 1 (MFT1):
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.
Brooke-Spiegler syndrome (BRSS):
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.

Ubiquitinated. Polyubiquitinated in hepatocytes treated with palmitic acid. Ubiquitination is mediated by E3 ligase TRIM47 and leads to proteasomal degradation.
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.