PSAT1 inhibits mTORC1 activation by preventing Rag heterodimer formation in lung adenocarcinoma

The mechanistic target of rapamycin complex 1 (mTORC1) integrates environmental cues, especially amino acids, to regulate metabolism and ultimately cancer progression. Phosphoserine aminotransferase 1 (PSAT1) is a key enzyme in de novo serine synthesis and its overexpression has been reported to promote oncogenesis in various cancers. Knockdown of PSAT1 inhibits the proliferation and migration of cancer cells. However, our study found an interesting phenomenon that either PSAT1 overexpression or knockout promoted cell proliferation in lung adenocarcinoma (LUAD) which seemed to contradict traditional views. The mechanism was that PSAT1 preferentially bound to GTP-loaded RagB GTPases, preventing the formation of Rag heterodimers. This restricted the lysosome localization of mTORC1 and enhanced the basal level of macroautophagy/autophagy, which promoted the proliferative ability of LUAD cells. PSAT1 knockout resulted in Rag heterodimer formation and mTORC1 activation, promoting protein synthesis and cell proliferation. Additionally, PSAT1 knockout caused a compensatory upregulation of the serine transporter solute carrier family 1 member 5 (SLC1A5), increasing exogenous serine uptake. In conclusion, our study reveals a novel function of PSAT1 in regulation of mTORC1 that affects the proliferation of LUAD cells. <b>Abbreviations</b>: ATG5: autophagy-related 5; BECN1: Beclin 1; CQ: chloroquine; 4EBP1: eukaryotic translation initiation factor 4E binding protein 1; GAP: GTPase-activating protein; GDP: Guanosine nucleotide diphosphate; GTP: Guanosine triphosphate; GTPase: guanosine triphosphatase; LAMP2: lysosome-associated membrane protein 2; LC3: microtubule-associated protein 1 light chain-3, LUAD: lung adenocarcinoma; mTORC1: mechanistic target of rapamycin complex 1; PCC: Pearson’s correlation coefficient; PSAT1: Phosphoserine aminotransferase 1; Rag: Ras-related GTP binding; Raptor: regulatory-associated protein of mTOR; S6: ribosomal protein S6; S6K1: substrates S6 kinase 1; SLC1A5: solute carrier family 1 member 5; SSP: serine biosynthetic pathway; ULK1: unc-51 like autophagy activating kinase 1.