Fig. 3

A schematic of AA sensors and signalling in metabolism. Sestrin-2 and LRS are cytosolic leucine sensors; arginine also has two sensors: a cytosol sensor - CASTOR1 and a lysosomal sensor - SLC38A9; methionine is indirectly sensed by SAM sensor – SAMTOR; Arf-1 relays the glutamine signals for mTORC1 activation. The methionine cycle and folate cycle are two functional modules connected and involved in one-carbon metabolism, which is involved in mitochondrial protein synthesis, nucleotide metabolism, glutathione and NAPDH syntheses. AA deficiency is sensed by GCN2 through binding to uncharged tRNA. GCN2 activation represses the translation of most mRNAs but selectively increases the translation of ATF4/GCN4. IFN-γ upregulates the tryptophan-catabolizing activity of IDO, while TGF-β can activate ARG1 in macrophages. The depletion of tryptophan or arginine leads to the proliferative arrest, anergy induction or apoptosis of T cells via GCN2 activation. ATF4 can upregulate AA metabolism including AA synthetases (including asparagine and serine), transporters (such as glutamine) and sensors (sestron-2) for cancer cell proliferation. Those words highlighted in red represent the upregulated biologic processes in cancer cells. LRS: leucyl-tRNA synthetase; SAM: S-adenosylmethionine; TPH: tryptophan hydroxylase; IDO: indoleamine 2,3-dioxygenase; TDO: tryptophan-2,3-dioxygenase; Arf-1: ADP ribosylation factor 1; IFN-γ: Interferon gamma; TGF-β: transforming growth factor beta