期刊
CELL REPORTS
卷 30, 期 8, 页码 2807-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.01.088
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资金
- National Natural Science Foundation of China [31870862, 31970700, 31700760, 31800751]
- National Key Basic Research Program of China [2015CB859800]
- Science and Technology Planning Project of Guangzhou, China [201804010385]
- Fundamental Research Funds for the Central Universities [18lgpy49, 18lgpy53]
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.
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