I kappa B Kinase epsilon-Dependent Phosphorylation and Degradation of X-Linked Inhibitor of Apoptosis Sensitizes Cells to Virus-Induced Apoptosis

X-linked inhibitor of apoptosis (XIAP) is a potent antagonist of caspase 3-, 7-, and 9-dependent apoptotic activities that functions as an E3 ubiquitin ligase, and it targets caspases for degradation. In this study, we demonstrate that Sendai virus (SeV) infection results in the IKK epsilon- or TBK1-mediated phosphorylation of XIAP in vivo at Ser430, resulting in Lys(48)-linked autoubiquitination at Lys322/328 residues, followed by the subsequent proteasomal degradation of XIAP. Interestingly, IKK epsilon expression and XIAP turnover increases SeV-triggered mitochondrion-dependent apoptosis via the release of caspase 3, whereas TBK1 expression does not increase apoptosis. Interestingly, phosphorylation also regulates XIAP interaction with the transcription factor IRF3, suggesting a role in IRF3-Bax-mediated apoptosis. Our findings reveal a novel function of IKK epsilon as a regulator of the virus-induced triggering of apoptosis via the phosphorylation-dependent turnover of XIAP.