Amino acids regulate mTORC1

MTOR, the kinase subunit of mTORC1, is activated by interaction with RHEB:GTP at the cytosolic face of lysosomal membrane. Recruitment of mTORC1 to the lysosomal membrane is intricate and incompletely understood. At the center of the system is a complex of two small GTPases, the Rag heterodimer (RRAGA or RRAGB bound to RRAGC or RRAGD). The Rag heterodimer is tethered to the membrane by the Ragulator complex, which also binds the v-ATPase complex. The Rag heterodimer acts as a cross-regulating switch, with the binding of GTP by one subunit inhibiting the exchange of GDP for GTP by the other subunit. The active conformation of the Rag heterodimer that recruits mTORC1 to the lysosomal membrane is RRAGA,B:GTP:RRAGC,D:GDP while the inactive conformation, RRAGA,B:GDP:RRAGC,D:GTP, releases mTORC1. GTPase activating proteins (GAPs) and guanyl nucleotide exchange factors (GEFs) acting upon the Rag heterodimer thereby regulate recruitment of mTORC1. RHEB:GTP at the lysosomal membrane also binds mTORC1 and directly activates mTORC1. During inactivation of mTORC1 in response to removal of amino acids, the TSC complex, a GAP for RHEB, is required in addition to the inactive Rag complex to release mTORC1 from RHEB and hence fully release mTORC1 from the lysosomal membrane.

Amino acids regulate recruitment of mTORC1 to the lysosomal membrane by at least 4 mechanisms (reviewed in Zhuang et al. 2019, Wolfson and Sabatini 2017, Yao et al. 2017). 1) Sestrin1 (SESN1) or Sestrin2 (SESN2) binds leucine and the Sestrin1,2:leucine complex is then released from the GATOR2 complex, allowing GATOR2 to positively regulate mTORC1 activation. 2) CASTOR1 in a homodimer or a heterodimer with CASTOR2 binds arginine and the CASTOR1:arginine complex is likewise released from GATOR2, allowing GATOR2 to activate mTORC1. 3) BMT2 (SAMTOR), a negative regulator of mTORC1 activation, binds S-adenosylmethionine (SAM), a derivative of methionine. The binding of SAM causes BMT2 to dissociate from GATOR1, allowing the activation of mTORC1. 4) The amino acid transporter SLC38A9 binds arginine and SLC38A9 then acts as a GEF to convert RRAGA,B:GDP to the active form, RRAGA,B:GTP. Amino acid starvation also regulates the assembly of the V0 and V1 subunits of v-ATPase by an uncharacterized mechanism and v-ATPase is required for activation of mTORC1 by amino acids. Glutamine activates mTORC1 by a mechanism that is independent of the Rag GTPases, requires ARF1, but is not yet fully elucidated.