CYLD deletion triggers nuclear factor-κB-signaling and increases cell death resistance in murine hepatocytes

Figure 6 Model of CYLD’s role in receptor mediated apoptosis or survival of hepatocytes. Binding of tumor necrosis factor (TNF)-α to TNF-R1 induces trimerisation and the recruitment of several adaptor proteins, including TRADD, RIP1 and TRAF2 to form the membrane-proximal complex I. K-63 Deubiquitination of RIP1 and TRAF2 by CYLD promotes the conversion of complex I to complex II building the death inducing signaling complex (DISC) leading to induction of apoptosis. K-63 polyubiquitinated RIP1 and TRAF2 facilitate nuclear factor (NF)-κB activation by the recruitment and activation of IKK and its activating kinase, Tak1[42]. Missing CYLD expression or a lack of CYLDs function leads to increased K-63 polyubiquitination of TRAF2 and RIP1 and therewith to a pronounced activation of the IKK complex. Activation of CD95 promotes recruitment of FADD, thereby assembling the DISC. RIP1 and TRAF2 are also known modulators of CD95 signaling[43]. The role of K-63 polyubiquitination and CYLD in the dynamic of CD95 mediated apoptosis and NF-κB induction is not clear. Known is, that cFLIP is involved in the connection of CD95 induced anti-apoptotic NF-κB signaling via its ability to activate IKK[44]. CYLD can remove K-63 polyubiquitin chains from the IKK regulatory subunit IKKγ thereby inhibiting IKK activation. Increased IKK activation by the absent of CYLD leads to inhibitor of NF-κB phosphorylation, K-48 polyubiquitination and following proteasomal degradation. Subsequently released NF-κB subunits can enter the nucleus to promote transcription of anti-apoptotic genes[42].