Regulation of mTORC1 by lysosomal calcium and calmodulin
- Johns Hopkins University School of Medicine, United States
- The University of Georgia, United States
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.
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Author details
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.
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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Regulation of mTORC1 by lysosomal calcium and calmodulin
eLife 5:e19360.
https://doi.org/10.7554/eLife.19360
