Regulation of mTORC1 by lysosomal calcium and calmodulin

eLife - Tập 5
Ruo‐Jing Li1,2, Jing Xu1,3,2, Chenglai Fu4, Jing Zhang5, Y. George Zheng5, Hao Jia6, Jun O. Liu7,1,2
1Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
2The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins University School of Medicine, Baltimore, United States
3Eli Lilly and Company, Indianapolis, United States
4The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
5Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, United States
6Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States
7Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States

Tóm tắt

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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