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Mol Cell. 2015 Jun 4;58(5):804-18. doi: 10.1016/j.molcel.2015.03.033. Epub 2015 Apr 30.

The ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation.

Author information

1
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
2
Department of Clinical Medicine, Shanghai Tenth People's Hospital of Tongji University, Tongji University, Shanghai 200072, China.
3
Institute of Aging Research, Hangzhou Normal University, Hangzhou 311121, China.
4
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Life Science and Technology, Tongji University, Shanghai 200072, China. Electronic address: pwangecnu@163.com.

Abstract

mTORC1 is essential for regulating cell growth and metabolism in response to various environmental stimuli. Heterodimeric Rag GTPases are required for amino-acid-mediated mTORC1 activation at the lysosome. However, the mechanism by which amino acids regulate Rag activation remains not fully understood. Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases. RNF152 knockout results in the hyperactivation of mTORC1 and protects cells from amino-acid-starvation-induced autophagy. Thus, this study reveals a mechanism for regulation of mTORC1 signaling by RNF152-mediated K63-linked polyubiquitination of RagA.

PMID:
25936802
DOI:
10.1016/j.molcel.2015.03.033
[Indexed for MEDLINE]
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