2. Academic Validation
  3. The ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation

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

  • Mol Cell. 2015 Jun 4;58(5):804-18. doi: 10.1016/j.molcel.2015.03.033.
Lu Deng 1,  Cong Jiang 1,  Lei Chen 1,  Jiali Jin 1,  Jie Wei 1,  Linlin Zhao 1,  Minghui Chen 1,  Weijuan Pan 1,  Yan Xu 1,  Hongshang Chu 1,  Xinbo Wang 1,  Xin Ge 2,  Dali Li 1,  Lujian Liao 1,  Mingyao Liu 1,  Li Li 3,  Ping Wang 4
Affiliations

Affiliations

  • 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.
PMID: 25936802 DOI: 10.1016/j.molcel.2015.03.033
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.

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