Cyld

CYLD is the acronym for "Cylindroma gene", a gene located on chromosome 16q12-q13, which was first discovered as a tumour suppressor gene. Its mutation is associated with various (benign) tumour types, such as autosomal-dominantly inherited cylindromes and multiple familial trichoepitheliomas.

The CYLD gene encodes a desubiquitinating enzyme, a deubiquitinase, which specifically cleaves 'Lys-63' and linear 'Met-1' linked polyubiquitin chains. The ability to remove linear ('Met-1'-linked) polyubiquitin chains regulates innate immunity and TNF-alpha-induced necroptosis, thereby establishing its tumour suppressor function. The enzyme thus acts as a regulator for various cellular processes such as the regulation of microtubule dynamics, cell proliferation, apoptosis, cell polarization, cell migration and angiogenesis. CYLD plays a role in the regulation of inflammation and the innate immune response via its effects on the activation of NF-KappaB.

The process of proteinubiquitination itself is a reversible reaction in which ubiquitin chains of a protein are deconjugated by specific deubiquitinases (= DUBs).

CYLD also supports STING signal transduction by stabilizing the STING protein (Zhang L et al. 2018). In addition, sCYLD regulates further signalling cascades such as the NFkB signalling pathway and the mitogen-activated protein kinase through its catalytic activity (Trompouki E et al. 2003).

Alternative splice forms of CYLD influence transcription factors and inflammatory processes. For example, sCYLD mediates the ubiquitination of SMAD7 and thus inhibits the TGF-beta signalling pathway. This inhibition leads to a promotion of inflammatory reactions, e.g. in inflammatory bowel diseases such as Crohn's disease.

1. Biggs PJ et al (1995) Familial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12-q13: evidence for its role as a tumour suppressor gene". Nature Genetics 11: 441-443
2. Mathis BJ et al (2015) CYLD-mediated signaling and diseases. Curr drug targets 16: 284-94
3. Trompouki E et al (2003) CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 424: 793-796
4. Zhang L et al (2018) The deubiquitinase CYLD is a specific checkpoint of the STING antiviral signaling pathway. PLoS pathogens 14: e1007435