Auto-ubiquitination of NEDD4-1 Recruits USP13 to Facilitate Autophagy through Deubiquitinating VPS34
Auto-ubiquitination of NEDD4-1 Recruits USP13 to Facilitate Autophagy through Deubiquitinating VPS34
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NEDD4-1 的自动泛素化招募 USP13 通过去泛素化 VPS34 促进自噬
DOI：
10.1016/j.celrep.2020.01.088
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发表时间：
2020-02-25
期刊：
影响因子：
8.8
通讯作者：
Cui, Jun
中科院分区：
文献类型：
--
作者：
Xie, Weihong;Jin, Shouheng;Cui, Jun
III类磷酸肌醇3-激酶空泡蛋白分选34（VPS 34）是自噬起始的核心蛋白，但对其严格控制的调控机制仍知之甚少。在这里，我们报告了E3泛素连接酶NEDD 4 -1通过靶向VPS 34促进自噬通量。NEDD 4 -1在K1279处经历赖氨酸29（K29）-连接的自身泛素化，并作为用于募集泛素特异性蛋白酶13（USP 13）以形成NEDD 4 -1-USP 13去泛素化复合物的支架，其随后通过在K419处从VPS 34去除K48-连接的多聚泛素链来稳定VPS 34以促进自噬。敲除NEDD 4 -1或USP 13增加了K48连接的泛素化和VPS 34的降解，从而减弱了自噬体的形成。我们的研究结果确定了NEDD 4 -1在调节自噬中的重要作用，这为泛素化调节自噬通量的机制提供了分子见解。
The class III phosphoinositide 3-kinase vacuolar protein sorting 34 (VPS34) is a core protein of autophagy initiation, yet the regulatory mechanisms responsible for its stringent control remain poorly understood. Here, we report that the E3 ubiquitin ligase NEDD4-1 promotes the autophagy flux by targeting VPS34. NEDD4-1 undergoes lysine 29 (K29)-linked auto-ubiquitination at K1279 and serves as a scaffold for recruiting the ubiquitin-specific protease 13 (USP13) to form an NEDD4-1-USP13 deubiquitination complex, which subsequently stabilizes VPS34 to promote autophagy through removing the K48-linked poly-ubiquitin chains from VPS34 at K419. Knockout of either NEDD4-1 or USP13 increased K48-linked ubiquitination and degradation of VPS34, thus attenuating the formation of the autophagosome. Our results identify an essential role for NEDD4-1 in regulating autophagy, which provides molecular insights into the mechanisms by which ubiquitination regulates autophagy flux.