Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Korea.
EMBO Rep. 2018 Apr;19(4). doi: 10.15252/embr.201744378. Epub 2018 Feb 27.
Autophagy begins with the formation of autophagosomes, a process that depends on the activity of the serine/threonine kinase ULK1 (hATG1). Although earlier studies indicated that ULK1 activity is regulated by dynamic polyubiquitination, the deubiquitinase involved in the regulation of ULK1 remained unknown. In this study, we demonstrate that ubiquitin-specific protease 20 (USP20) acts as a positive regulator of autophagy initiation through stabilizing ULK1. At basal state, USP20 binds to and stabilizes ULK1 by removing the ubiquitin moiety, thereby interfering with the lysosomal degradation of ULK1. The stabilization of basal ULK1 protein levels is required for the initiation of starvation-induced autophagy, since the depletion of USP20 by RNA interference inhibits LC3 puncta formation, a marker of autophagic flux. At later stages of autophagy, USP20 dissociates from ULK1, resulting in enhanced ULK1 degradation and apoptosis. Taken together, our findings provide the first evidence that USP20 plays a crucial role in autophagy initiation by maintaining the basal expression level of ULK1.
自噬始于自噬体的形成，这一过程依赖于丝氨酸/苏氨酸激酶 ULK1（hATG1）的活性。尽管早期的研究表明 ULK1 的活性受到动态多泛素化的调节，但参与调节 ULK1 的去泛素化酶仍不清楚。在这项研究中，我们证明了泛素特异性蛋白酶 20（USP20）通过稳定 ULK1 作为自噬起始的正调节剂发挥作用。在基础状态下，USP20 通过去除泛素部分与 ULK1 结合并稳定 ULK1，从而干扰 ULK1 的溶酶体降解。基础 ULK1 蛋白水平的稳定对于饥饿诱导的自噬的起始是必需的，因为 RNA 干扰消耗 USP20 会抑制 LC3 斑点的形成，这是自噬通量的标志物。在自噬的后期阶段，USP20 从 ULK1 上解离，导致 ULK1 降解和凋亡增强。总之，我们的研究结果提供了第一个证据，表明 USP20 通过维持基础状态下 ULK1 的表达水平在自噬起始中发挥关键作用。
