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
  • 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: [email protected].
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.