MCRS1 Binds and Couples Rheb to Amino Acid-Dependent mTORC1 Activation

• MCRS1 interacts with Rheb and activates mTORC1
• MCRS1 is essential for mTORC1 activity and its associated cellular functions
• MCRS1 maintains Rheb at lysosomes in active GTP-bound form to activate mTORC1
• Absence of amino acids and MCRS1 delocalizes lysosomal Rheb but not lysosomal TSC2

SummaryRas homolog enriched in brain (Rheb) is critical for mechanistic target of rapamycin complex 1 (mTORC1) activation in response to growth factors and amino acids (AAs). Whereas growth factors inhibit the tuberous sclerosis complex (TSC1-TSC2), a negative Rheb regulator, the role of AAs in Rheb activation remains unknown. Here, we identify microspherule protein 1 (MCRS1) as the essential link between Rheb and mTORC1 activation. MCRS1, in an AA-dependent manner, maintains Rheb at lysosome surfaces, connecting Rheb to mTORC1. MCRS1 suppression in human cancer cells using small interference RNA or mouse embryonic fibroblasts using an inducible-Cre/Lox system reduces mTORC1 activity. MCRS1 depletion promotes Rheb/TSC2 interaction, rendering Rheb inactive and delocalizing it from lysosomes to recycling endocytic vesicles, leading to mTORC1 inactivation. These findings have important implications for signaling mechanisms in various pathologies, including diabetes mellitus and cancer.

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