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

Abstract

Ras 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.

Regulation of mTORC1 by PI3K signaling

“…A subpopulation of Rheb, which tethers to membranes through a farnesyl lipid modification, resides at the lysosome [65,126-128]. Farnesylation of Rheb provides a relatively weak membrane anchor but is essential for robust mTORC1 signaling [27].…”

“…Rag binding does not directly activate mTORC1 but instead serves to bring it into proximity with lysosomally localized Rheb. A major pool of the TSC complex has also been identified at the lysosome and dynamic regulation of its localization here holds the key to Rheb activation [65,75,128,129]. In the absence of growth factors, the TSC complex accumulates at the lysosome [65,75].…”

“…In the absence of growth factors, the TSC complex accumulates at the lysosome [65,75]. But in response to growth factor-stimulated PI3K signaling, phosphorylation of TSC2 by Akt induces the TSC complex to abruptly dissociate from this compartment and move to an undefined cellular location [65,128]. Importantly, mutating the five Akt-targeted sites on TSC2 to non-phosphorylatable residues, or fusing a lysosomal targeting sequence to TSC2 to lock it at the lysosome, is sufficient to make TSC complex localization and mTORC1 signaling insensitive to growth factor-PI3K signaling [65].…”

The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging

“…Recent work has found that other cellular stresses, including a lack of amino acids, similarly promote lysosomal accumulation of TSC through a mechanism that may be partially dependent on the Rag GTPases (Demetriades et al, 2014; Demetriades et al, 2016). Interestingly, the lysosomal recruitment of the Rheb GTPase itself is also regulated by amino acids, which stimulate the binding of Rheb to microspherule protein 1 (MCRS1) (Fawal et al, 2015). The localization of Rheb-MCRS1 to the lysosome depends upon both amino acids and the presence of an active Ragulator and v-ATPase.…”

“…The localization of Rheb-MCRS1 to the lysosome depends upon both amino acids and the presence of an active Ragulator and v-ATPase. In addition to its localization function, MCRS regulates the association of Rheb with TSC1/2 in an amino acid dependent manner (Fawal et al, 2015). The intricate ballet by which mTORC1 and its activators are localized to the lysosome, while its inhibitors depart (Figure 3), highlights the necessity for precise coordination of upstream signals with downstream cellular responses.…”