Recent Advances in Understanding Amino Acid Sensing Mechanisms that Regulate mTORC1

Abstract

The mammalian target of rapamycin (mTOR) is the central regulator of mammalian cell growth, and is essential for the formation of two structurally and functionally distinct complexes: mTORC1 and mTORC2. mTORC1 can sense multiple cues such as nutrients, energy status, growth factors and hormones to control cell growth and proliferation, angiogenesis, autophagy, and metabolism. As one of the key environmental stimuli, amino acids (AAs), especially leucine, glutamine and arginine, play a crucial role in mTORC1 activation, but where and how AAs are sensed and signal to mTORC1 are not fully understood. Classically, AAs activate mTORC1 by Rag GTPases which recruit mTORC1 to lysosomes, where AA signaling initiates. Plasma membrane transceptor L amino acid transporter 1 (LAT1)-4F2hc has dual transporter-receptor function that can sense extracellular AA availability upstream of mTORC1. The lysosomal AA sensors (PAT1 and SLC38A9) and cytoplasmic AA sensors (LRS, Sestrin2 and CASTOR1) also participate in regulating mTORC1 activation. Importantly, AAs can be sensed by plasma membrane receptors, like G protein-coupled receptor (GPCR) T1R1/T1R3, and regulate mTORC1 without being transported into the cells. Furthermore, AA-dependent mTORC1 activation also initiates within Golgi, which is regulated by Golgi-localized AA transporter PAT4. This review provides an overview of the research progress of the AA sensing mechanisms that regulate mTORC1 activity.

Keywords: amino acids; mTORC1; membrane receptor; membrane transceptor; sensor.

Figure 1

Model of mTOR signaling network in mammalian cells. It consists of two functionally different complexes known as mTORC1 and mTORC2. The mTORC1 pathway integrates inputs from at least three major cues, namely AAs, growth factors (such as IGF1 and insulin) and energy status, to regulate many major processes, including protein synthesis and autophagy. mTORC1 signaling is highly sensitive to AAs, which can be transported into cells through plasma membrane AATs, and then exert their regulatory roles. AA-dependent activation of mTORC1 requires small Rag GTPases. There are four Rag proteins that work in heterodimers. Rag A or B binds to Rag C or D. Upon growth factor stimulation, mTORC1 signaling is activated through the classical PI3K-PKB/Akt-TSC-Rheb pathway. Energy status is also sensed upstream of mTORC1. Low energy activates AMPK, which inhibits mTORC1 function by phosphorylating and activating TSC2 as well as phosphorylating Raptor. Arrows represent activation, whereas bars represent inhibition. mTOR: mammalian target of rapamycin; mTORC1: mTOR complex 1; IGF1: insulin-like growth factor 1; AAs: amino acids; AATs: AA transporters; PI3K: phosphatidylinositide 3-kinase; PKB/Akt: protein kinase B; TSC: tuberous sclerosis complex; Rheb: Ras homolog enriched in brain; Raptor: regulatory-associated protein of mTOR; AMPK: AMP-activated protein kinase.

Figure 2

Bidirectional transport of AAs regulates mTORC1 activity. ASCT2 transports glutamine into the cell to increase its intracellular concentration. LAT1-4F2hc is a bidirectional transporter that mediates the simultaneous efflux of glutamine out of cells and uptake of extracellular leucine, which in turn activates mTORC1 signaling. AAs: amino acids; mTORC1: mammalian target of rapamycin complex 1; ASCT2: system ASC AA transporter 2; LAT1: system L amino acid transporter 1; 4F2hc: heavy chain of 4F2 cell surface antigen.

Figure 3

Model of AA-dependent activation of mTORC1 from LELs and Golgi apparatus. Multiple sensors are involved, including transporters (PAT1, PAT4 and SLC38A9) and cytosolic sensors (LRS, Sestrin2 and CASTOR1), which can sense specific AAs to activate mTORC1 on the surface of LELs or Golgi. Classically, mTORC1 is activated by AAs at LELs. Leucine activates Rag-mTORC1 by binding to LRS, which activates LRS GAP activity towards RagD, and by binding to Sestrin2, which inhibits Sestrin2-GATOR2 interaction. Arginine also promotes the activation of mTORC1 through binding to lysosome AA transporter SLC38A9 and CASTOR1. Activation of PI3K/Akt/Rheb signaling promotes the shuttling of PAT1 from the cell membrane to LEL membranes. PAT1 directionally transports AAs and protons out of the LELs coupled by the pumping of the protons back into the LEL lumen by v-ATPase, which subsequently leads to mTORC1 activation. Furthermore, AAs (perhaps glutamine and serine) also activate mTORC1 via stimulating interaction of AA transporter PAT4 with mTORC1 and its regulators Rab1A and Rheb on the Golgi. Arrows represent activation, whereas bars represent inhibition. AAs: amino acids; mTORC1: mammalian target of rapamycin complex 1; LELs: late endosomes and lysosomes; PAT1/4: proton-assisted AA transporters 1/4; LRS: leucyl-tRNA synthetase; CASTOR1: cellular arginine sensor for mTORC1; GATOR1/2: GAP activity towards Rags 1/2; PI3K: phosphatidylinositide 3-kinase; PKB/Akt: protein kinase B; Rheb: Ras homolog enriched in brain.