Rheb and Rags come together at the lysosome to activate mTORC1

Abstract

mTORC1 (mammalian target of rampamycin complex 1) is a highly conserved protein complex regulating cell growth and metabolism via its kinase mTOR (mammalian target of rapamycin). The activity of mTOR is under the control of various GTPases, of which Rheb and the Rags play a central role. The presence of amino acids is a strict requirement for mTORC1 activity. The heterodimeric Rag GTPases localize mTORC1 to lysosomes by their amino-acid-dependent interaction with the lysosomal Ragulator complex. Rheb is also thought to reside on lysosomes to activate mTORC1. Rheb is responsive to growth factors, but, in conjunction with PLD1 (phospholipase D1), is also an integral part of the machinery that stimulates mTORC1 in response to amino acids. In the present article, we provide a brief overview of novel mechanisms by which amino acids affect the function of Rags. On the basis of existing literature, we postulate that Rheb is activated at the Golgi from where it will travel to lysosomes. Maturation of endosomes into lysosomes may be required to assure a continuous supply of GTP-bound Rheb for mTORC1 activation, which may help to drive the maturation process.

Evolving Perspectives of mTOR Complexes in Immunity and Transplantation

“…Metabolic processes regulated by mTORC1 include protein, lipid and mitochondrial biosynthesis and autophagy ( Figure 1). Other than regulation of mTORC1 via growth factor signaling through PI3K, amino acids directly modulate mTORC1 in a PI3K-independent fashion (17,18). Critical proteins include a group of four recombinaseactivating gene (Rag) guanosine-5 0 -triphosphate (GTP) ases that form heterodimers and recruit mTORC1 to lysosomes when in their GTP-bound form.…”

Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9

“…The TSC is composed of the proteins TSC1, TSC2, and TBC1D7 and acts as a GTPase-activating protein (GAP) for the small GTPase RHEB (Ras homolog enriched in brain), stimulating the transition from its active GTP-bound to its inactive GDP-bound state (5-7). RHEB is anchored to endomembranes, especially to lysosomes, via its prenylated C-terminal CAAX box motif and promotes mTORC1 kinase activity in its GTP-bound state (8)(9)(10)(11)(12)(13)(14).Nutrient sensing is a key upstream signal for mTORC1 regulation, as growth factors or hormones are not sufficient to fully activate mTORC1 (9, 15). Whereas mTOR is dispersed within the cell upon amino acid starvation, amino acid replenishment redistributes mTOR to active, GTP-bound RHEB at the lysosomal surface (9).…”

Autophagic Pathology and Calcium Deregulation in Neurodegeneration

“…In response to amino acids, mTORC1 has been reported to be recruited to the lysosomal surface by Rag GTPases [35]. Such lysosomal localization seems to be required for activation of the complex by Rheb [36]. The active mTORC1 complex promotes cell growth and inhibits autophagy by inhibitory phosphorylation of the mammalian Atg1 orthologues ULK1 and ULK2 (ULK1/2) and Atg13 subunits [37] (Fig.…”