AMBRA1 Interplay with Cullin E3 Ubiquitin Ligases Regulates Autophagy Dynamics
AMBRA1 Interplay with Cullin E3 Ubiquitin Ligases Regulates Autophagy Dynamics
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DOI：
10.1016/j.devcel.2014.11.013
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发表时间：
2014-12-22
影响因子：
11.8
通讯作者：
Fimia, Gian Maria
中科院分区：
文献类型：
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作者：
Antonioli, Manuela;Albiero, Federica;Fimia, Gian Maria
自噬通过降解有害或不必要的细胞内成分来维持细胞稳态。如何快速且短暂地诱导自噬反应仍然很大程度上未知。我们报道，E3 泛素连接酶 Cullin-5 和 Cullin-4 通过与自噬调节因子 AMBRA1 动态相互作用，分别调节自噬的开始和终止。在正常条件下，Cullin-4 与 AMBRA1 的结合限制了其蛋白质丰度。自噬刺激通过引起 ULK1 依赖性 Cullin-4 释放来促进 AMBRA1 稳定。值得注意的是，Cullin-4/AMBRA1 解离是短暂的，重新建立的相互作用会触发 AMBRA1 降解，从而终止自噬反应。此外，Cullin-4 抑制 AMBRA1 和另一种 Cullin E3 连接酶之间的相互作用。事实上，在 Cullin-4 解离后，AMBRA1 结合并抑制 Cullin-5，从而促进 mTOR 抑制剂 DEPTOR 的积累。通过 DEPTOR 稳定，AMBRA1 建立了一个反馈回路，通过增强 mTOR 失活来确保自噬的快速启动。我们的研究结果表明，Cullin 介导的自噬调节因子降解暂时控制着自噬反应。
Autophagy maintains cellular homeostasis by degrading harmful or unnecessary intracellular components. How the autophagy response is induced rapidly and transiently remains largely unknown. We report that the E3 ubiquitin ligases Cullin-5 and Cullin-4 regulate the onset and termination of autophagy, respectively, by dynamically interacting with AMBRA1, a regulator of autophagy. Under normal conditions, Cullin-4 binding to AMBRA1 limits its protein abundance. Autophagy stimuli promote AMBRA1 stabilization by causing ULK1-dependent Cullin-4 release. Notably, Cullin-4/AMBRA1 dissociation is transient, and the re-established interaction triggers AMBRA1 degradation, terminating the autophagy response. Moreover, Cullin-4 inhibits the interaction between AMBRA1 and another Cullin E3 ligase. Indeed, upon Cullin-4 dissociation, AMBRA1 binds and inhibits Cullin-5, thus promoting the accumulation of the mTOR inhibitor DEPTOR. Through DEPTOR stabilization, AMBRA1 establishes a feedback loop that ensures the rapid onset of autophagy by enhancing mTOR inactivation. Our findings show that Cullin-mediated degradation of autophagy regulators temporally controls the autophagy response.