CYLD (cylindromatosis (turban tumor syndrome))

	Figure 1. CYLD gene. Coding exons are indicated in dark red. Asterisks indicate exons which are differentially spliced. One of the exon which is alternatively present (Reiley et al., 2004) encodes the binding site for TRAF2 and NEMO (Hövelmeyer et al., 2007).
Description	21 exons (17 coding) with alternative splicing (see figure 1). Size of the exons: 74 (bp), 98, 79, 136, 626, 302, 105, 8, 98, 116, 379, 165, 141, 122, 91, 66, 132, 108, 118, 216, 5611. The whole gene extends over approximately 56 kb.
Pseudogene	No.

	Figure 2. Structural organisation of CYLD. Binding sites for TRAF2 and NEMO are indicated. CAP: CAP-Gly domain, P: phosphorylation site, C and H: subdomains of the catalytic domain containing the Cys and His active residues.
Description	956 aa, approximately 110 kD. Member of the deubiquitinase family (USP (Ubiquitin Specific Protease)) (Reyes-Turcu et al., 2009) with preferential affinity for K63-linked polyubiquitin chains (Massoumi and Paus, 2007; Courtois, 2008).
Expression	Ubiquitous.
Localisation	Cytoplasm (might bind to microtubules through its CAP-Gly domains).
Function	CYLD has been primarily identified as a negative regulator of NF-kappaB signaling, able to bind NEMO and TRAF2 and to deubiquitinate them (Brummelkamp et al., 2003; Kovalenko et al., 2003; Trompouki et al., 2003). It is also a negative regulator of JNK and p38 signaling pathways (Reiley et al., 2004) and IRF-3 signaling pathways (Friedman et al., 2008; Zhang et al., 2008). It participates in antimicrobial defense and inflammation by targeting ubiquitinated TRAF6 (Lim et al., 2007; Lim et al., 2008) and is required for the development and activation of immune cells (Reiley et al., 2006; Jin et al., 2007). CYLD may also affect cell proliferation/cell cycling by targeting Plk1 and HDAC6 (Stegmeier et al., 2007; Massoumi et al., 2009) and cell migration via microtubule assembly (Gao et al., 2008). It controls spermatogenesis by deubiquitinating RIP (Wright et al., 2007) and osteoclastogenesis by deubiquitinating TAK1 (Jin et al., 2008). A role for CYLD in the hypoxia response has been reported (An et al., 2008). Its inactivation by human papilloma virus-derived E6 protein results in hypoxia-induced NF-kappaB activation. Finally, it has been shown to affect calcium channel function by deubiquitinating TRPA1 (Stokes et al., 2006). CYLD interacts with NEMO (Kovalenko et al., 2003; Trompouki et al., 2003), TRAF2 (Kovalenko et al., 2003; Trompouki et al., 2003), p62 (Wooten et al., 2008), Bcl-3 (Massoumi et al., 2006), TAK1 (Reiley et al., 2007), RIP (Wright et al., 2007), lck (Reiley et al., 2006), HDAC6 (Wickström et al., 2010).
Homology	Catalytic box (with other members of the deubiquitinase family (USPs)) and CAP-Gly (with a small collection of proteins (Steinmetz and Akhmanova, 2008)).

	Figure 3. Mutations of CYLD. Misense mutations are indicated by boxes, nonsense mutations by black brackets and frameshift mutations by orange bars. Compiled from Blake and Toro, 2009 with additions from Amaro et al., 2009; Kazakov et al., 2009; Nasti et al., 2009; Wang et al., 2010 and Kazakov et al., 2010.
Germinal	Tumor suppressor (Bignell et al., 2000). See full recent listing in Blake and Toro, 2009. Most of the mutations (non sense, frameshit, splicing) would produce large deletions of the protein but, most likely, produce mRNA nonsense-mediated decay. Short truncations affect the catalytic box which extends to the carboxy-terminus of the protein and produce an inactive enzyme. Very few missense mutations have been reported. All of them affect the catalytic box.
Somatic	Loss of heterozygosity in developing tumors.

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