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

Zhenzhen Zi1, Zhuzhen Zhang2, Qiang Feng3

  • 1Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

Nature Communications
|April 2, 2022
PubMed

Insights

The mechanistic target of rapamycin complex 1 (mTORC1) phosphorylates STK11IP on lysosomes, inhibiting autophagy. STK11IP dephosphorylation activates autophagy, offering a therapeutic target for metabolic diseases.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Metabolism

Background:

  • The serine/threonine kinase mTORC1 regulates cell growth and proliferation, and is activated on lysosomal surfaces.
  • The precise role of mTORC1 in phosphorylating local lysosomal proteins to control lysosomal biology remains unclear.

Purpose of the Study:

  • To investigate whether mTORC1 phosphorylates lysosomal proteins to regulate lysosomal biology.
  • To identify lysosome-specific substrates of mTORC1 and elucidate their function.

Main Methods:

  • Cross-reference analysis of lysosome proteome and mTORC1-regulated phosphoproteome.
  • STK11IP knockout and dephosphorylation studies in mice.
  • V-ATPase activity assays.

Main Results:

  • STK11IP was identified as a lysosome-specific substrate of mTORC1, phosphorylated at Ser404.
  • STK11IP knockout significantly increased autophagy flux.
  • STK11IP binds to and regulates V-ATPase activity, impacting lysosomal acidification and autophagy.
  • STK11IP knockout protected mice against fatty liver induced by fasting or a methionine/choline-deficient diet.

Conclusions:

  • STK11IP phosphorylation by mTORC1 is a novel mechanism regulating lysosomal acidification and autophagy.
  • STK11IP acts as an autophagy inhibitor, and its dephosphorylation at Ser404 represses this function.
  • Targeting STK11IP offers a potential therapeutic strategy for diseases characterized by dysregulated autophagy.

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