Selective degradation of IKKα by autophagy is essential for arsenite-induced cancer cell apoptosis
Selective degradation of IKKα by autophagy is essential for arsenite-induced cancer cell apoptosis
复制标题
自噬选择性降解 IKK α 对于亚砷酸盐诱导的癌细胞凋亡至关重要
DOI：
10.1038/s41419-020-2420-5
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发表时间：
2020-04-07
影响因子：
9
通讯作者：
Song Lun
中科院分区：
文献类型：
--
作者：
Tan Qixing;Zou Shuxian;Song Lun
IKK复合物的两个催化亚基IKK α和IKK β在生理和病理条件下触发NF-κ B活化以及NF-κ B非依赖性信号传导事件。在这里，我们确定了NF-κ B无关的细胞保护功能的IKK α在促进自噬通过触发p53反式激活和上调其下游自噬介质，DRAM 1，在亚砷酸盐处理的肝癌细胞，其响应依赖于IKK α激酶活性。此外，IKK α通过诱导CHK 1活化和CHK 1/p53相互作用触发p53/DRAM 1依赖性自噬。有趣的是，在引发自噬后，IKK α可以通过与LC 3B直接结合而被自噬机制特异性识别，导致IKK α通过自噬选择性降解。出乎意料的是，对IKK α的自噬螯合的选择性是由新的机制介导的，独立于IKK α内的经典LC 3相互作用区域（LIR），而LIR的C-末端臂参与介导IKK α/LC 3B相互作用。综上所述，我们得出结论，IKK α通过诱导p53依赖性自噬减弱亚砷酸盐诱导的细胞凋亡，然后通过自噬选择性反馈降解IKK α有助于亚砷酸盐诱导的细胞毒性反应。
Two catalytic subunits of the IKK complex, IKK alpha and IKK beta, trigger NF-kappa B activation as well as NF-kappa B-independent signaling events under both physiological and pathological conditions. Here we identified the NF-kappa B-unrelated cytoprotective function of IKK alpha in promoting autophagy by triggering p53 transactivation and upregulation of its downstream autophagic mediator, DRAM1, in the arsenite-treated hepatoma cells, which responses depended on IKK alpha kinase activity. Furthermore, IKK alpha triggered p53/DRAM1-dependent autophagy by inducing CHK1 activation and CHK1/p53 interaction. Interestingly, after provoking autophagy, IKK alpha could be specifically recognized by the autophagic machinery via directly binding with LC3B, resulting in selective degradation of IKK alpha by autophagy. Unexpectedly, the selectivity of autophagic sequestration towards IKK alpha was mediated by novel mechanism independent of the classical LC3-interacting regions (LIRs) within IKK alpha, while C-terminal arm of LIR was involved in mediating IKK alpha/LC3B interaction. Taken together, we conclude that IKK alpha attenuates arsenite-induced apoptosis by inducing p53-dependent autophagy, and then selective feedback degradation of IKK alpha by autophagy contributes to the cytotoxic response induced by arsenite.