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Regulation of mTORC1 by lysosomal calcium and calmodulin

Ruo-Jing Li1,2, Jing Xu1,2,3, Chenglai Fu4

  • 1Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States.

Elife
|October 28, 2016
PubMed

Insights

Lysosomal calcium release via TRPML1 is essential for mTORC1 activation. Calmodulin (CaM) binds mTOR in a calcium-dependent manner, revealing mTOR as a novel CaM-dependent kinase.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Lysosomal lipid accumulation impairs calcium release, inhibiting mTORC1 signaling.
  • The precise mechanism linking lysosomal calcium to mTORC1 regulation remained unclear.

Purpose of the Study:

  • To elucidate the role of lysosomal calcium and TRPML1 in mTORC1 signaling.
  • To identify the molecular players mediating calcium's effect on mTORC1.

Main Methods:

  • Investigated mTORC1 activity in cells with altered TRPML1 expression (depletion/overexpression).
  • Utilized pharmacological activators/inhibitors of TRPML1 and calmodulin (CaM).
  • Assessed the interaction between mTOR and CaM, and CaM's effect on mTOR kinase activity in vitro.

Main Results:

  • TRPML1 depletion reduced mTORC1 activity; TRPML1 activation increased it.
  • Lysosomal calcium promotes mTORC1 activation by inducing calmodulin (CaM) binding to mTOR.
  • CaM antagonists inhibited mTORC1 activity, and CaM stimulated mTORC1 kinase activity in a calcium-dependent manner.

Conclusions:

  • TRPML1-mediated lysosomal calcium release is critical for mTORC1 activation.
  • mTOR is identified as a novel calmodulin-dependent kinase.
  • TRPML1, lysosomal calcium, and CaM are key regulators of the mTORC1 pathway.
Keywords:
biochemistrycalciumcalmodulinhumanmTOR

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