Institute of Military Cognitive and Brain Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
Department of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei 230032, P. R. China.
J Cell Sci. 2020 Nov 16;133(22):jcs246868. doi: 10.1242/jcs.246868.
In our previous report, we demonstrated that one of the catalytic subunits of the IκB kinase (IKK) complex, IKKα (encoded by ), 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 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 IκB 激酶（IKK）复合物的一个催化亚基 IKKα（由 编码）在人肝癌细胞中，在抗肿瘤治疗试剂亚砷酸盐的治疗下，发挥非 NF-κB 依赖性的细胞保护作用。IKKα 通过激活依赖 p53 的自噬来触发自身降解，作为一个反馈回路，因此为亚砷酸盐诱导的肝癌细胞凋亡做出了重大贡献。有趣的是，IKKα 不能直接与 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 位）方面发挥关键作用。在本研究中，我们发现 p53 乙酰化（Lys373 和/或 Lys382 位）对于自噬的诱导和亚砷酸盐反应中 IKKα 的自噬降解也至关重要。此外，IKKα 通过与 p53 的乙酰转移酶 p300（也称为 EP300）和 CBP（也称为 CREBBP）（统称为 p300/CBP）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，IKKα 和 CHK1 依赖性 p53 磷酸化和乙酰化都有助于介导选择性自噬反馈降解 IKKα 在亚砷酸盐诱导的促凋亡反应中。
