TY - JOUR
T1 - Quantitative phosphoproteomic analyses identify STK11IP as a lysosome-specific substrate of mTORC1 that regulates lysosomal acidification
AU - Zi, Zhenzhen
AU - Zhang, Zhuzhen
AU - Feng, Qiang
AU - Kim, Chiho
AU - Wang, Xudong
AU - Scherer, Philipp E.
AU - Gao, Jinming
AU - Levine, Beth
AU - Yu, Yonghao
N1 - Funding Information:
The Yu lab receives or has received research funding from Pfizer and Biosplice Therapeutics.
Funding Information:
We thank Drs. Qing Zhong, Xiaonan Dong, and Joseph Albanesi for the helpful discussions. We thank Dr. Hamid Baniasadi for the help with metabolomic studies, Metabolomics Core Facility within the Biochemistry Department. We thank the UT Southwestern Mouse Metabolic Phenotyping Core and Carlos Castorena for the assistance with mice treadmill exercise studies. We also thank the University of Texas Southwestern Medical Center McDermott Center Next Generation Sequencing Core, Flow Cytometry Core of the Children?s Research Institute, Histopathology Core, Live Cell Imaging Core, Electron Microscope Core, and Animal Resource Center. This work was supported in part by grants from the Welch Foundation (I-1800 to Y.Y.), NIH (R35GM134883, R01NS122533, and R21CA261018 to Y.Y.), and CPRIT (RP160157 to Z.Z.).
Funding Information:
We thank Drs. Qing Zhong, Xiaonan Dong, and Joseph Albanesi for the helpful discussions. We thank Dr. Hamid Baniasadi for the help with metabolomic studies, Metabolomics Core Facility within the Biochemistry Department. We thank the UT Southwestern Mouse Metabolic Phenotyping Core and Carlos Castorena for the assistance with mice treadmill exercise studies. We also thank the University of Texas Southwestern Medical Center McDermott Center Next Generation Sequencing Core, Flow Cytometry Core of the Children’s Research Institute, Histopathology Core, Live Cell Imaging Core, Electron Microscope Core, and Animal Resource Center. This work was supported in part by grants from the Welch Foundation (I-1800 to Y.Y.), NIH (R35GM134883, R01NS122533, and R21CA261018 to Y.Y.), and CPRIT (RP160157 to Z.Z.).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-29461-8
DO - 10.1038/s41467-022-29461-8
M3 - Article
C2 - 35365663
AN - SCOPUS:85127444298
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1760
ER -