Substrate-specific regulation of the mTORC1 pathway by G protein-coupled receptors

The mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) orchestrates cell growth and metabolism in response to diverse external cues. mTORC1 has a myriad of phosphorylation substrates, each playing important physiological roles. Emerging evidence suggests that mTORC1 can respond to upstream signals in a nuanced manner, enabling differential regulation of individual substrates and downstream biological processes. However, the nature of signals that determine the signaling selectivity of mTORC1 remains incompletely understood. Here, we studied mTORC1 regulation by G protein-coupled receptors (GPCRs). We found that phosphorylation of the Transcription Factor EB (TFEB), a non-canonical mTORC1 substrate that controls lysosome biogenesis, responds to GPCRs differently, compared to canonical mTORC1 substrates controlling protein synthesis such as S6K1 and 4EBP1. In particular, the muscarinic acetylcholine receptor M5 (M5R) promoted phosphorylation of S6K1 and 4EBP1, while triggering TFEB dephosphorylation. Consequently, M5R stimulated protein synthesis without inhibiting lysosome biogenesis. The regulations of an anabolic process and a catabolic process, albeit both governed by mTORC1, are thus decoupled downstream of M5R. This study highlights the importance of reassessing the effects of GPCRs on mTORC1 by concurrently monitoring individual substrates, a critical consideration to be made when evaluating GPCR ligands as therapeutic agents targeting the mTORC1 pathway.