Regulation of mTORC1 by lysosomal calcium and calmodulin

被引：110
作者：
Li, Ruo-Jing [1 ,2 ]
Xu, Jing [1 ,2 ,3 ]
Fu, Chenglai [4 ]
Zhang, Jing [5 ]
Zheng, Yujun George [5 ]
Jia, Hao [6 ]
Liu, Jun O. [1 ,2 ,7 ]
机构：
[1] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, SJ Yan & HJ Mao Lab Chem Biol, Baltimore, MD 21218 USA
[3] Eli Lilly & Co, Indianapolis, IN 46285 USA
[4] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD USA
[5] Univ Georgia, Coll Pharm, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA
[6] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA
[7] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA
来源：
ELIFE | 2016年 / 5卷
基金：
美国国家卫生研究院;
关键词：
ACTIVATED PROTEIN-KINASE; INTRACELLULAR CALCIUM; S6; KINASE; INDEPENDENT PATHWAY; MAMMALIAN TARGET; RAG GTPASES; RAPAMYCIN; GROWTH; PHOSPHORYLATION; RAPTOR;
D O I：
10.7554/eLife.19360
中图分类号：
Q [生物科学];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
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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页数：16
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