2. Academic Validation
  3. Regulation of mTORC1 by lysosomal calcium and calmodulin

Regulation of mTORC1 by lysosomal calcium and calmodulin

  • Elife. 2016 Oct 27;5:e19360. doi: 10.7554/eLife.19360.
Ruo-Jing Li 1 2,  Jing Xu 1 2 3,  Chenglai Fu 4,  Jing Zhang 5,  Yujun George Zheng 5,  Hao Jia 6,  Jun O Liu 1 2 7
Affiliations

Affiliations

  • 1 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States.
  • 2 The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins University School of Medicine, Baltimore, United States.
  • 3 Eli Lilly and Company, Indianapolis, United States.
  • 4 The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States.
  • 5 Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, United States.
  • 6 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States.
  • 7 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States.
PMID: 27787197 DOI: 10.7554/eLife.19360
Abstract

Blockade of lysosomal calcium release due to lysosomal lipid accumulation has been shown to inhibit mTORC1 signaling. However, the mechanism by which lysosomal calcium regulates mTORC1 has remained undefined. Herein we report that proper lysosomal calcium release through the Calcium Channel TRPML1 is required for mTORC1 activation. TRPML1 depletion inhibits mTORC1 activity, while overexpression or pharmacologic activation of TRPML1 has the opposite effect. Lysosomal calcium activates mTORC1 by inducing association of Calmodulin (CaM) with mTOR. Blocking the interaction between mTOR and CaM by antagonists of CaM significantly inhibits mTORC1 activity. Moreover, CaM is capable of stimulating the kinase activity of mTORC1 in a calcium-dependent manner in vitro. These results reveal that mTOR is a new type of CaM-dependent kinase, and TRPML1, lysosomal calcium and CaM play essential regulatory roles in the mTORC1 signaling pathway.

Keywords

biochemistry; calcium; calmodulin; human; mTOR.

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