Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) is the key signaling hub that regulates cellular protein homeostasis, growth, and proliferation in health and disease. As a prerequisite for activation of mTORC1 by hormones and mitogens, there first has to be an available pool of intracellular amino acids. Arginine, an amino acid essential during mammalian embryogenesis and early development is one of the key activators of mTORC1. Herein, we demonstrate that arginine acts independently of its metabolism to allow maximal activation of mTORC1 by growth factors via a mechanism that does not involve regulation of mTORC1 localization to lysosomes. Instead, arginine specifically suppresses lysosomal localization of the TSC complex and interaction with its target small GTPase protein, Rheb. By interfering with TSC-Rheb complex, arginine relieves allosteric inhibition of Rheb by TSC. Arginine cooperates with growth factor signaling which further promotes dissociation of TSC2 from lysosomes and activation of mTORC1. Arginine is the main amino acid sensed by the mTORC1 pathway in several cell types including human embryonic stem cells (hESCs). Dependence on arginine is maintained once hESCs are differentiated to fibroblasts, neurons, and hepatocytes, highlighting the fundamental importance of arginine-sensing to mTORC1 signaling. Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signaling.DOI: http://dx.doi.org/10.7554/eLife.11058.001

Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination

“…Conversely, energy deficiency-activated adenosine monophosphate protein kinase (AMPK; PRKA) triggers the phosphorylation of TSC2-T1227/S1387, enhancing TSC1/2 activity and inhibiting mTORC1. Recently, arginine has been shown to activate mTORC1 via a RAG GTPase-independent mechanism (Carroll et al, 2016). mTORC2 In contrast to mTORC1, the factors and regulative processes driving mTORC2 activation remain relatively understudied.…”

“…mTORC1 activation is induced by amino acids, particularly leucine, glutamine and arginine through both RAG GTPase-dependent and -independent mechanisms (Jewell et al, 2015;Carroll et al, 2016), and also activates feedback mechanisms that further increase nutrient uptake to fuel anabolic reactions. Conversely, upon starvation, mTORC1 activity is reduced, alleviating the repression of ULK1/2.…”

“…Deficiency of autophagy in ESCs under such stress conditions leads to apoptosis or detrimental accumulation of pluripotency-associated proteins that compromise the pluripotent state (Mizushima et al, 2001;Cho et al, 2014). Expanding on the crucial role of mTORC1 in nutrient sensing, several amino acid pathways have been reported to be essential for the maintenance of PSC properties Carroll et al, 2016;Shiraki et al, 2014;Carey et al, 2015). Pluripotent mESCs are dependent on threonine catabolism by threonine dehydrogenase (TDH) for the synthesis of SAM, which in turn regulates histone methylations that drive ESC self-renewal and pluripotency ShyhChang et al, 2013).…”

TOR Signaling in Budding Yeast

“…On the other hand, a previous study reported that amino acid deprivation recruited the TSC complex to the lysosome [63], suggesting that the amino acid-dependent activation of mTORC1 is regulated by an interplay between the Rag GTPases-Ragulator branch and the TSC complex-Rheb branch. A recent study reported that Arg is required for the growth factor-dependent delocalization of the TSC complex from the lysosome, which leads to the activation of Rheb, and, thus, mTORC1 [64] (Figure 2). …”

Rheb in neuronal degeneration, regeneration, and connectivity

“…Rag-GTPase-mediated translocation of mTORC1 to the lysosomes, brings it into close proximity of Rheb, which stimulates the kinase activity of mTOR (Sancak et al, 2008;Groenewoud and Zwartkruis, 2013;Demetriades et al, 2014). Among the amino acids that control mTORC1 activity, arginine and leucine appear to be important (Carroll et al, 2016). Furthermore, Fawal et al, identified microspherule protein 1 (MCRS1) as an essential protein whose depletion allows Figure 1: Rheb-mTORC1 signaling is activated in response to various intracellular and extracellular signals in the nervous system.…”