Regulation of mTORC1 by lysosomal calcium and calmodulin

Ruo Jing Li, Jing Xu, Chenglai Fu, Jing Zhang, Yujun George Zheng, Hao Jia, Jun Liu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournaleLife
Volume5
DOIs
StatePublished - Oct 27 2016

Fingerprint

Calmodulin
Calcium
Phosphotransferases
Chemical activation
Calcium-Calmodulin-Dependent Protein Kinases
mechanistic target of rapamycin complex 1
Calcium Channels
Thermodynamic properties
Association reactions
Lipids

Keywords

  • biochemistry
  • calcium
  • calmodulin
  • human
  • mTOR

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Li, R. J., Xu, J., Fu, C., Zhang, J., Zheng, Y. G., Jia, H., & Liu, J. (2016). Regulation of mTORC1 by lysosomal calcium and calmodulin. eLife, 5. https://doi.org/10.7554/eLife.19360

Regulation of mTORC1 by lysosomal calcium and calmodulin. / Li, Ruo Jing; Xu, Jing; Fu, Chenglai; Zhang, Jing; Zheng, Yujun George; Jia, Hao; Liu, Jun.

In: eLife, Vol. 5, 27.10.2016.

Research output: Contribution to journalArticle

Li, RJ, Xu, J, Fu, C, Zhang, J, Zheng, YG, Jia, H & Liu, J 2016, 'Regulation of mTORC1 by lysosomal calcium and calmodulin', eLife, vol. 5. https://doi.org/10.7554/eLife.19360
Li RJ, Xu J, Fu C, Zhang J, Zheng YG, Jia H et al. Regulation of mTORC1 by lysosomal calcium and calmodulin. eLife. 2016 Oct 27;5. https://doi.org/10.7554/eLife.19360
Li, Ruo Jing ; Xu, Jing ; Fu, Chenglai ; Zhang, Jing ; Zheng, Yujun George ; Jia, Hao ; Liu, Jun. / Regulation of mTORC1 by lysosomal calcium and calmodulin. In: eLife. 2016 ; Vol. 5.
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