Ragulator Is a GEF for the Rag GTPases that Signal Amino Acid Levels to mTORC1

SummaryThe mTOR Complex 1 (mTORC1) pathway regulates cell growth in response to numerous cues, including amino acids, which promote mTORC1 translocation to the lysosomal surface, its site of activation. The heterodimeric RagA/B-RagC/D GTPases, the Ragulator complex that tethers the Rags to the lysosome, and the v-ATPase form a signaling system that is necessary for amino acid sensing by mTORC1. Amino acids stimulate the binding of guanosine triphosphate to RagA and RagB but the factors that regulate Rag nucleotide loading are unknown. Here, we identify HBXIP and C7orf59 as two additional Ragulator components that are required for mTORC1 activation by amino acids. The expanded Ragulator has nucleotide exchange activity toward RagA and RagB and interacts with the Rag heterodimers in an amino acid- and v-ATPase-dependent fashion. Thus, we provide mechanistic insight into how mTORC1 senses amino acids by identifying Ragulator as a guanine nucleotide exchange factor (GEF) for the Rag GTPases.

Graphical AbstractFigure optionsDownload high-quality image (204 K)Download as PowerPoint slideHighlights
► C7orf59 and HBXIP are required for amino acid sensing by the mTORC1 pathway
► C7orf59 and HBXIP are additional components the Ragulator complex
► Ragulator is a GEF for the RagA and RagB GTPases
► The v-ATPase controls Ragulator function in cells in response to amino acids