Autophagy regulates apoptosis by targeting NOXA for degradation
Autophagy regulates apoptosis by targeting NOXA for degradation
复制标题
自噬通过靶向 NOXA 降解来调节细胞凋亡
DOI：
10.1016/j.bbamcr.2018.05.007
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发表时间：
2018-08-01
影响因子：
5.1
通讯作者：
Zhao, Yongchao
中科院分区：
文献类型：
--
作者：
Wang, Jingchao;Cui, Danrui;Zhao, Yongchao
细胞凋亡和自噬相互调节细胞的各种生理和病理过程。自噬和凋亡之间的相互作用是多方面的和复杂的。阐明它们相互作用的分子机制将推进自噬在治疗癌症和其他疾病方面的治疗应用。NOXA是BCL-2家族中仅有BH 3的成员，据报道可诱导细胞凋亡并促进自噬。在这里，我们报道了自噬通过靶向NOXA降解来调节细胞凋亡。抑制自噬通过延长蛋白质半衰期来增加NOXA蛋白质水平。NOXA积累通过诱导细胞凋亡有效地抑制肿瘤细胞生长，当p53存在时，细胞凋亡进一步增强。从机制上讲，NOXA被p62劫持为自噬货物，其C末端的三个赖氨酸残基是溶酶体中NOXA降解所必需的。总之，我们的研究表明，NOXA是自噬和凋亡之间相互作用的桥梁，这意味着自噬抑制剂可能是癌症的有效疗法，特别是含有野生型p53的癌症。
Apoptosis and autophagy mutually regulate various cellular physiological and pathological processes. The crosstalk between autophagy and apoptosis is multifaceted and complicated. Elucidating the molecular mechanism of their crosstalk will advance the therapeutic applications of autophagy for treating cancer and other diseases. NOXA, a BH3-only member of the BCL-2 family, was reported to induce apoptosis and promote autophagy. Here, we report that autophagy regulates apoptosis by targeting NOXA for degradation. Inhibiting autophagy increases NOXA protein levels by extending the protein half-life. NOXA accumulation effectively suppresses tumor cell growth by inducing apoptosis, which is further enhanced when p53 is present. Mechanistically, NOXA is hijacked by p62 as autophagic cargo, and its three lysine residues at the C-terminus are necessary for NOXA degradation in lysosomes. Taken together, our study demonstrates that NOXA serves as a bridge in the crosstalk between autophagy and apoptosis and implies that autophagy inhibitors could be an effective therapy for cancer, especially wild-type p53-containing cancer.