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

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.
Mesh Terms:
Amino Acid Sequence, Animals, Autophagy, Enzyme Activation, HEK293 Cells, Humans, Lysosomes, Mice, Knockout, Molecular Sequence Data, Monomeric GTP-Binding Proteins, Multiprotein Complexes, Phosphorylation, Protein Transport, Signal Transduction, TOR Serine-Threonine Kinases, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination
Mol. Cell
Date: Jun. 04, 2015
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