TOR-mediated Ypt1 phosphorylation regulates autophagy initiation complex assembly.

The EMBO journal 2023 Oct 04

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The regulation of autophagy initiation is a key step in autophagosome biogenesis. However, our understanding of the molecular mechanisms underlying the stepwise assembly of ATG proteins during this process remains incomplete. The Rab GTPase Ypt1/Rab1 is recognized as an essential autophagy regulator. Here, we identify Atg23 and Atg17 as binding partners of Ypt1, with their direct interaction proving crucial for the stepwise assembly of autophagy initiation complexes. Disruption of Ypt1-Atg23 binding results in significantly reduced Atg9 interactions with Atg11, Atg13, and Atg17, thus preventing the recruitment of Atg9 vesicles to the phagophore assembly site (PAS). Likewise, Ypt1-Atg17 binding contributes to the PAS recruitment of Ypt1 and Atg1. Importantly, we found that Ypt1 is phosphorylated by TOR at the Ser174 residue. Converting this residue to alanine blocks Ypt1 phosphorylation by TOR and enhances autophagy. Conversely, the Ypt1S174D phosphorylation mimic impairs both PAS recruitment and activation of Atg1, thus inhibiting subsequent autophagy. Thus, we propose TOR-mediated Ypt1 as a multifunctional assembly factor that controls autophagy initiation via its regulation of the stepwise assembly of ATG proteins. © 2023 The Authors.

Citation

Weijing Yao, Yuting Chen, Yingcong Chen, Pengwei Zhao, Jing Liu, Yi Zhang, Qiang Jiang, Choufei Wu, Yu Xie, Siyu Fan, Miao Ye, Yigang Wang, Yuyao Feng, Xue Bai, Mingzhu Fan, Shan Feng, Juan Wang, Yixian Cui, Hongguang Xia, Cheng Ma, Zhiping Xie, Liqin Zhang, Qiming Sun, Wei Liu, Cong Yi. TOR-mediated Ypt1 phosphorylation regulates autophagy initiation complex assembly. The EMBO journal. 2023 Oct 04;42(19):e112814