Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling

Abstract

Germline mutations in the cylindromatosis (CYLD) gene have been described in families with cylindromas, trichoepitheliomas, and/or spiradenomas. Brooke-Spiegler syndrome (BSS) is the autosomal dominant predisposition to skin appendageal neoplasms including cylindromas, trichoepitheliomas, and/or spiradenomas. We review the clinical features, molecular genetics, and the animal models of BSS. To date, a total of 51 germline CYLD mutations have been reported, occurring in exons 9-20, in 73 families with diverse ethnic and racial backgrounds. Of 51 mutations, 86% are expected to lead to truncated proteins. The seven missense mutations reported to date occur only within the ubiquitin (Ub)-specific protease (USP) domain of the CYLD protein and most are associated exclusively with multiple familial trichoepithelioma (MFT). CYLD functions as a tumor suppressor gene. CYLD encodes a deubiquitinating (DUB) enzyme that negatively regulates the nuclear factor (NF)-kappaB and c-Jun N-terminal kinase (JNK) pathways. CYLD DUB activity is highly specific for lysine 63 (K63)-linked Ub chains but has been shown to act on K48-linked Ub chains as well. In 2008, the CYLD USP domain was crystallized, revealing that the truncated Fingers subdomain confers CYLD's unique specificity for K63-linked Ub chains. Recent work using animal models revealed new roles for CYLD in immunity, lipid metabolism, spermatogenesis, osteoclastogenesis, antimicrobial defense, and inflammation.

Figure 1. CYLD germline mutations associated with BSS

A, reported CYLD mutations, *indicates recurrent mutations; B, CYLD exons, not drawn to scale; C, CYLD protein domains, drawn to scale; D, CYLD USP subdomains, drawn to scale; E, reported CYLD missense mutations. Figure based on the published GenBank sequence NM_015247.2

Figure 2. CYLD in cell signaling

Model of how CYLD regulates different signaling pathways regulating survival, proliferation and inflammation in different cell types through deubiquitination. Dotted arrows denote multistep or incomplete pathways. CYLD and its known binding partners are in white font. Targets activated by CYLD are in green. Key targets for CYLD include removal of K63-linked Ub from TRAF2 and TRAF6, proteins that form a complex for NF-kB signaling. CYLD also deubiquitinates RIP1, a protein that associates with TRAF2. Deubiquitination of TRAF2 inhibits MKK7 activation and downstream JNK signaling. Deubiquitination of TRAF2, TRAF6, TRAF7 and TAK1 inhibit downstream dissociation of IKK from NF-kB and NF-KB signaling. In addition, deubiquitination of TRAF6 also inhibits downstream activation of RANK signaling and internalization of the TRKA receptor. CYLD interaction with TRAF6 requires the adaptor protein p62. In response to dsRNA, RIG-I is activated. CYLD DUB of RIG-I and TBK1 inhibits downstream activation of IRF3 signaling. RIG-I is a known activator of NF-kB as well. CYLD deubiquitination of BCL3 prevents its translocation from the cytoplasm to the nucleus in response to UV light. Nuclear BCL-3 activates cyclinD1 and promotes cell proliferation. CYLD also activates cyclinD1, possibly through PLK1. CYLD associates with the calcium channel, TRPA1, and maintains its activation by removing ubiquitin.