Cylindromatosis protein
Cylindromatosis (CYLD) protein was originally identified as a tumour suppressor involved in familial cylindromatosis [63]. CYLD is also involved, however, in diverse physiological processes ranging from immunity and inflammation to cell cycle progression, spermatogenesis, and osteoclastogenesis (reviewed in [64]). CYLD is a deubiquitinating enzyme that negatively regulates NF-κB signalling initiated by TNFR, RANK and T-cell receptor stimulation (reviewed in [64]) (Figure 1), by deubiquitina-ting several NF-κB signalling proteins including NEMO, TRAF2, TRAF6, TRAF7, RIP1 and TAK1. Many of these are also targeted by A20 and it is still not clear why the cell needs A20 as well as CYLD to control NF-κB activation. As A20 is only expressed in many cell types upon stimulation, it has been suggested that this protein mainly regulates later phases of NF-κB signalling, whereas CYLD would regulate constitutive and early signalling. In addition, their relative activity might also be cell-type dependent [64].
Interestingly, CYLD has been shown to negatively regulate RANK signalling and osteoclastogenesis in mice [65]. Mice with a genetic deficiency of CYLD have aberrant osteoclast differentiation and develop severe osteoporosis. Osteoclast precursors of these mice are hyper-responsive to RANKL-induced differentiation and produce more and larger osteoclasts. CYLD expression is markedly upregulated under conditions of RANKL-induced osteoclastogenesis and is recruited to ubiquitinated TRAF6 via the ubiquitin-binding adaptor protein p62 (also known as sequestosome 1) [65], followed by the CYLD-mediated deubiquitination of TRAF6. In this context, it is worth mentioning that transgenic mice expressing a mutated form of p62 also display abnormal osteoclastogenesis and develop progressive bone loss [66]. These findings suggest that CYLD-mediated inhibi-tion of RANK-induced NF-κB signalling plays a key role in the negative regulation of osteoclastogenesis and indicate CYLD as a potential genetic factor involved in the pathology of bone disorders such as RA.