The Ubiquitination of RagA GTPase by RNF152 Negatively Regulates mTORC1 Activation

• DOI: 10.1016/j.molcel.2015.03.033
• Publication Date: 2015-05-02T22:18:48Z
• Authors: Lu Deng; Cong Jiang; Lei Chen; Jiali Jin; Jie Wei; Linlin Zhao; Minghui Chen; Weijuan Pan; Yan Xu; Hongshang Chu; Xinbo Wang; Xin Ge; Dali Li; Lujian Liao; Mingyao Liu; Li Li; Ping Wang
• Keywords: Mice, Knockout; 0301 basic medicine; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Molecular Sequence Data; Ubiquitination; Cell Biology; Mechanistic Target of Rapamycin Complex 1; Tuberous Sclerosis Complex 1 Protein; Enzyme Activation; Protein Transport; 03 medical and health sciences; HEK293 Cells; Multiprotein Complexes; Autophagy; Animals; Humans; Amino Acid Sequence; Phosphorylation; Lysosomes; Molecular Biology; Monomeric GTP-Binding Proteins; Signal Transduction

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.