Auto-ubiquitination of NEDD4-1 Recruits USP13 to Facilitate Autophagy through Deubiquitinating VPS34

• Published in: Cell reports (Cambridge) Vol. 30; no. 8; pp. 2807 - 2819.e4
• Main Authors: Xie, Weihong, Jin, Shouheng, Wu, Yaoxing, Xian, Huifang, Tian, Shuo, Liu, Di-Ao, Guo, Zhiyong, Cui, Jun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.02.2020; Elsevier
• Subjects: auto-ubiquitination; Autophagy; Cell Line; Class III Phosphatidylinositol 3-Kinases - metabolism; deubiquitination complex; Enzyme Stability; Humans; Lysine - metabolism; Nedd4 Ubiquitin Protein Ligases - metabolism; NEDD4-1; Protein Binding; Ubiquitin-Specific Proteases - metabolism; Ubiquitination; USP13; VPS34; USP13; autophagy; NEDD4-1; VPS34; deubiquitination complex; auto-ubiquitination
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.01.088

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. [Display omitted] •NEDD4-1 promotes autophagy through inhibiting K48-linked ubiquitination of VPS34•NEDD4-1 recruits USP13 to deubiquitinate VPS34•Auto-ubiquitination of NEDD4-1 is required for its interaction with USP13 and VPS34 Xie et al. demonstrate that HECT ubiquitin E3 ligase NEDD4-1 undergoes lysine 29 (K29)-linked auto-ubiquitination and serves as a scaffold to recruit the ubiquitin-specific protease 13 (USP13) to form a deubiquitination complex, which subsequently stabilizes VPS34 to promote autophagy through the removal of K48-linked poly-ubiquitin chains on VPS34.