mTOR-mediated phosphorylation of VAMP8 and SCFD1 regulates autophagosome maturation

Hong Huang, Qinqin Ouyang, Min Zhu, Haijia Yu, Kunrong Mei and Rong Liu ()
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Hong Huang: Nanjing Agricultural University
Qinqin Ouyang: Nanjing Agricultural University
Min Zhu: College of Life Sciences, Nanjing Normal University
Haijia Yu: College of Life Sciences, Nanjing Normal University
Kunrong Mei: Tianjin University
Rong Liu: Nanjing Agricultural University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract The mammalian target of rapamycin (mTORC1) has been shown to regulate autophagy at different steps. However, how mTORC1 regulates the N-ethylmaleimide-sensitive protein receptor (SNARE) complex remains elusive. Here we show that mTORC1 inhibits formation of the SNARE complex (STX17-SNAP29-VAMP8) by phosphorylating VAMP8, thereby blocking autophagosome-lysosome fusion. A VAMP8 phosphorylation mimic mutant is unable to promote autophagosome-lysosome fusion in vitro. Furthermore, we identify SCFD1, a Sec1/Munc18-like protein, that localizes to the autolysosome and is required for SNARE complex formation and autophagosome-lysosome fusion. VAMP8 promotes SCFD1 recruitment to autolysosomes when dephosphorylated. Consistently, phosphorylated VAMP8 or SCFD1 depletion inhibits autophagosome-lysosome fusion, and expression of phosphomimic VAMP8 leads to increased lipid droplet accumulation when expressed in mouse liver. Thus, our study supports that mTORC1-mediated phosphorylation of VAMP8 blocks SCFD1 recruitment, thereby inhibiting STX17-SNAP29-VAMP8 complex formation and autophagosome-lysosome fusion.

Date: 2021
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DOI: 10.1038/s41467-021-26824-5

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