Quantitative phosphoproteomic analyses identify STK11IP as a lysosome-specific substrate of mTORC1 that regulates lysosomal acidification

Zhenzhen Zi, Zhuzhen Zhang, Qiang Feng, Chiho Kim, Xu-Dong Wang, Philipp E. Scherer, Jinming Gao, Beth Levine and Yonghao Yu ()
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Zhenzhen Zi: University of Texas Southwestern Medical Center
Zhuzhen Zhang: University of Texas Southwestern Medical Center
Qiang Feng: University of Texas Southwestern Medical Center
Chiho Kim: University of Texas Southwestern Medical Center
Xu-Dong Wang: University of Texas Southwestern Medical Center
Philipp E. Scherer: University of Texas Southwestern Medical Center
Jinming Gao: University of Texas Southwestern Medical Center
Beth Levine: University of Texas Southwestern Medical Center
Yonghao Yu: University of Texas Southwestern Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract The evolutionarily conserved serine/threonine kinase mTORC1 is a central regulator of cell growth and proliferation. mTORC1 is activated on the lysosome surface. However, once mTORC1 is activated, it is unclear whether mTORC1 phosphorylates local lysosomal proteins to regulate specific aspects of lysosomal biology. Through cross-reference analyses of the lysosome proteome with the mTORC1-regulated phosphoproteome, we identify STK11IP as a lysosome-specific substrate of mTORC1. mTORC1 phosphorylates STK11IP at Ser404. Knockout of STK11IP leads to a robust increase of autophagy flux. Dephosphorylation of STK11IP at Ser404 represses the role of STK11IP as an autophagy inhibitor. Mechanistically, STK11IP binds to V-ATPase, and regulates the activity of V-ATPase. Knockout of STK11IP protects mice from fasting or Methionine/Choline-Deficient Diet (MCD)-induced fatty liver. Thus, our study demonstrates that STK11IP phosphorylation represents a mechanism for mTORC1 to regulate lysosomal acidification and autophagy, and points to STK11IP as a promising therapeutic target for the amelioration of diseases with aberrant autophagy signaling.

Date: 2022
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DOI: 10.1038/s41467-022-29461-8

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