1. Biochemistry and Chemical Biology
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Regulation of mTORC1 by lysosomal calcium and calmodulin

  1. Ruo-Jing Li
  2. Jing Xu
  3. Chenglai Fu
  4. Jing Zhang
  5. Yujun George Zheng
  6. Hao Jia
  7. Jun O Liu  Is a corresponding author
  1. Johns Hopkins University School of Medicine, United States
  2. The University of Georgia, United States
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Cite this article as: eLife 2016;5:e19360 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.

Article and author information

Author details

  1. Ruo-Jing Li

    Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jing Xu

    Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Chenglai Fu

    The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4300-9948
  4. Jing Zhang

    Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yujun George Zheng

    Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Hao Jia

    Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jun O Liu

    Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
    For correspondence
    joliu@jhu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3842-9841

Funding

National Institutes of Health (CA184103)

  • Ruo-Jing Li
  • Jing Xu
  • Chenglai Fu
  • Jing Zhang
  • Yujun George Zheng
  • Hao Jia
  • Jun O Liu

Flight Attendant Medical Research Institute (NA)

  • Ruo-Jing Li
  • Jing Xu
  • Chenglai Fu
  • Jing Zhang
  • Yujun George Zheng
  • Hao Jia
  • Jun O Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Michael Czech, University of Massachusetts Medical School, United States

Publication history

  1. Received: July 4, 2016
  2. Accepted: October 26, 2016
  3. Accepted Manuscript published: October 27, 2016 (version 1)
  4. Version of Record published: November 11, 2016 (version 2)

Copyright

© 2016, Li et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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