Autophagy is inhibited by ubiquitin ligase activity in the nervous system
Autophagy is inhibited by ubiquitin ligase activity in the nervous system
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DOI：
10.1038/s41467-019-12804-3
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发表时间：
2019-11-01
影响因子：
16.6
通讯作者：
Grill, Brock
中科院分区：
文献类型：
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作者：
Crawley, Oliver;Opperman, Karla J.;Grill, Brock
自噬是细胞内的分解代谢过程，在饥饿、衰老和疾病中表现突出。神经元自噬尤其重要，因为它影响神经系统的发育和功能，并与神经退行性疾病密切相关。尽管如此，神经元中自噬是如何被调节的仍然知之甚少。使用无偏倚的蛋白质组学方法，我们证明了自噬的主要启动物UNC-51/ULK激酶受到泛素连接酶RPM-1的负调控。RPM-1泛素连接酶活性限制特定轴突室内UNC-51和自噬体的形成，并在整个神经系统广泛发挥作用。RPM-1通过抑制UNC-51活性，抑制自噬体形成，影响轴突终止、突触维持和行为习惯。这些结果证明了UNC-51和自噬是如何在轴突中受到亚细胞调节的，并揭示了整个神经系统中限制自噬起始的机制。鉴于自噬调节改变与神经退行性疾病之间的联系日益密切，我们的发现具有重要的意义，超出了神经系统发育的范畴。
Autophagy is an intracellular catabolic process prominent in starvation, aging and disease. Neuronal autophagy is particularly important, as it affects the development and function of the nervous system, and is heavily implicated in neurodegenerative disease. Nonetheless, how autophagy is regulated in neurons remains poorly understood. Using an unbiased proteomics approach, we demonstrate that the primary initiator of autophagy, the UNC-51/ULK kinase, is negatively regulated by the ubiquitin ligase RPM-1. RPM-1 ubiquitin ligase activity restricts UNC-51 and autophagosome formation within specific axonal compartments, and exerts effects broadly across the nervous system. By restraining UNC-51 activity, RPM-1 inhibits autophagosome formation to affect axon termination, synapse maintenance and behavioral habituation. These results demonstrate how UNC-51 and autophagy are regulated subcellularly in axons, and unveils a mechanism for restricting initiation of autophagy across the nervous system. Our findings have important implications beyond nervous system development, given growing links between altered autophagy regulation and neurodegenerative diseases.