Autophagic feedback-mediated degradation of IKKα requires CHK1/p300/CBP-dependent acetylation of p53.

In our previous report, we demonstrated that one of the catalytic subunits of the I-κB kinase (IKK) complex, IKKα, performs an NF-κB-independent cytoprotective role in human hepatoma cells under the treatment of the anti-tumor therapeutic reagent arsenite. IKKα triggers its own feedback degradation by activating p53-dependent autophagy and therefore contributes largely to hepatoma cell apoptosis induced by arsenite. Interestingly, IKKα is unable to interact with p53 directly but plays a critical role in mediating p53 phosphorylation (at Ser15) by promoting CHK1 activation and CHK1/p53 complex formation. In the current study, we found that p53 acetylation (at Lys373/382) was also critical for the induction of autophagy and the autophagic degradation of IKKα in the arsenite responses. Furthermore, IKKα was involved in p53 acetylation through interaction with the acetyltransferases for p53, p300 and CBP, inducing CHK1-dependent p300/CBP activation and promoting p300/p53 or CBP/p53 complex formation. Therefore, taken together with the previous report, we conclude that both IKKα- and CHK1-dependent p53 phosphorylation and acetylation contribute to mediating selective autophagy targeting feedback degradation of IKKα in arsenite-induced proapoptotic responses.