The mTORC1 complex acts as an integrator that regulates translation, lipid synthesis, autophagy, and cell growth in response to multiple inputs, notably glucose, oxygen, amino acids, and growth factors such as insulin (reviewed in Sabatini 2017, Meng et al. 2018, Kim and Guan 2019).
MTOR, the kinase subunit of mTORC1, is activated by interaction with RHEB:GTP at the cytosolic face of lysosomal membrane (Long et al. 2005, Tee et al. 2005, Long et al. 2007, Yang et al. 2017). 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 (Shen et al. 2017). 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 (Sancak et al. 2008, Kim et al. 2008, Sancak et al. 2010, Lawrence et al. 2018). 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 (Demetriades et al. 2014).
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 (Chantranupong et al. 2014, Parmigiani et al. 2014, Kim et al. 2015, Wolfson et al. 2016, Saxton et al. 2016). 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 (Chantranupong et al. 2016, Saxton et al. 2016, Gai et al. 2016, Xia et al. 2016). 3) BMT2 (SAMTOR), a negative regulator of mTORC1 activation, binds S-adenosylmethionine (SAM), a derivative of methionine (Gu et al. 2017). 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 (Rebsamen et al. 2015, Wang et al. 2015, Wyant et al. 2017, Shen and Sabatini 2018). Amino acid starvation also regulates the assembly of the V0 and V1 subunits of v-ATPase by an uncharacterized mechanism (Stransky and Forgac 2015) and v-ATPase is required for activation of mTORC1 by amino acids (Zoncu et al. 2011). Glutamine activates mTORC1 by a mechanism that is independent of the Rag GTPases, requires ARF1, but is not yet fully elucidated (Jewell et al. 2015).