Cellular response to starvation

EIF2AK4 (GCN2) senses amino acid deficiency by binding uncharged tRNAs near the ribosome, and phosphorylating EIF2S1 (reviewed in Chaveroux et al. 2010, Castilho et al. 2014, Gallinetti et al. 2013, Bröer and Bröer 2017, Wek 2018). This reduces translation of most mRNAs but increases translation of mRNAs, notably ATF4, that mediate stress responses (reviewed in Kilberg et al. 2012, Wortel et al. 2017; Dever and Hinnebusch 2005).

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. This process is regulated by various individual amino acids (reviewed in Zhuang et al. 2019, Wolfson and Sabatini 2017, Yao et al. 2017) and is reversed in response to the removal of amino acids, through the action of TSC1.