Auto-ubiquitination of NEDD4-1 Recruits USP13 to Facilitate Autophagy through Deubiquitinating VPS34
- Cell Rep. 2020 Feb 25;30(8):2807-2819.e4. doi: 10.1016/j.celrep.2020.01.088.
- 1. MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
- 2. Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
- 3. MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China. Electronic address: [email protected].
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.