随着NF-κB非相关性IKK激酶底物分子被不断发现，IKK激酶的两个催化亚基——IKKa和IKKb的效应机制研究已远远超出了NF-κB的经典范畴。申请人长期开展“细胞应激损伤反应中的NF-κB非相关性IKK激酶新功能机制”探索，并在近期工作中发现了以砷化物为代表的细胞毒性化学刺激剂诱导细胞凋亡反应过程中存在有IKKb和NF-κB非相关的“IKKa对细胞自噬反应的调控作用及反作用”。一方面砷化物能够通过激活IKKa并进一步活化p53从而引发p53依赖的细胞自噬反应并发挥细胞凋亡保护效应；另一方面自噬反应被诱导后可选择性降解IKKa从而终止以上保护效应并最终诱导细胞走向凋亡。本课题拟对“IKKa-p53-自噬-IKKa降解”负反馈信号通路诱导活化的信号传递机制及其在介导细胞毒性化学刺激剂诱导促细胞凋亡反应中的贡献及意义进行分析，以期揭示应激损伤条件下IKKa参与自噬反应调控的新模式和新机制。

With the discovery of more and more NF-kB-independent signaling molecules whose activities are regulated by the catalytic subunits of IKK complex, IKKa and IKKb, the biological roles for these two IKK subunits have gone far beyond NF-kB activation. One of the research interests of our group is to disclose the novel NF-kB-independent functions of IKKa and IKKb in response to the stress signals. In our recent study, we found that IKKa played a key role in regulating autophagy, the lysosomal degradation process, in response to the treatment of cytotoxic chemical reagents, such as arsenite, cisplatin, VP-16 and 5-Fu. Notably, this effect of IKKa was proved to be unrelated to IKKb and NF-kB activities, but was delivered by the activation of p53 pathway in the arsenite-induced response. Furthermore, IKKa could be selectively degraded by autophagy after activation and this feed-back control of IKKa is critical for mediating the pro-apoptotic effect of arsenite. Therefore, disclosing the signaling events involving in controlling the activation of "IKKa-p53-autophagy-autophagic degradation of IKKa" feed-back loop and their contribution to the cell apoptotic effects induced by arsneite and other cytotoxic reagents are important to extend our knowledge on the NF-kB-independent role for IKKa involving in regualting autophagy under stress conditions.