In our previous report, we demonstrated that one of the catalytic subunits of the IB kinase (IKK) complex, IKKα (encoded by CHUK), performs an NF-B-independent cytoprotective role in human hepatoma cells under the treatment of the anti-tumor therapeutic reagent arsenite. IKKα triggers its own degradation, as a feedback loop, by activating p53-dependent autophagy, and therefore contributes substantially 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 and/or Lys382) was also critical for the induction of autophagy and the autophagic degradation of IKKα during the arsenite response. Furthermore, IKKα was involved in p53 acetylation through interaction with the acetyltransferases for p53, p300 (also known as EP300) and CBP (also known as CREBBP) (collectively p300/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 feedback degradation of IKKα during the arsenite-induced proapoptotic responses.

在我们之前的报告中，我们证明了 IB 激酶 (IKK) 复合物的催化亚基之一 IKKα（由CHUK编码）在抗肿瘤药物治疗下对人肝癌细胞发挥独立于 NF-B 的细胞保护作用治疗试剂亚砷酸盐。IKKα 通过激活 p53 依赖性自噬，作为反馈回路触发其自身降解，因此对亚砷酸盐诱导的肝癌细胞凋亡有重大贡献。有趣的是，IKKα 无法直接与 p53 相互作用，但通过促进 CHK1 激活和 CHK1-p53 复合物形成，在介导 p53 磷酸化（Ser15）方面发挥关键作用。在当前的研究中，我们发现 p53 乙酰化（Lys373 和/或 Lys382）对于亚砷酸盐反应期间 IKKα 的自噬诱导和自噬降解也至关重要。此外，IKKα 通过与 p53、p300（也称为 EP300）和 CBP（也称为 CREBBP）（统称为 p300/CBP）的乙酰转移酶相互作用，参与 p53 乙酰化，诱导 CHK1 依赖性 p300/CBP 激活并促进 p300– p53 或 CBP-p53 复合物形成。因此，结合之前的报告，我们得出结论，在亚砷酸盐诱导的促凋亡反应中，IKKα 和 CHK1 依赖性 p53 磷酸化和乙酰化都有助于介导 IKKα 的选择性自噬反馈降解。