Metabolism of glucose activates TORC1 through multiple mechanisms in Saccharomyces cerevisiae

Summary Target of Rapamycin Complex 1 (TORC1) is a conserved eukaryotic protein complex that links the presence of nutrients with cell growth. In Saccharomyces cerevisiae , TORC1 activity is positively regulated by the presence of amino acids and glucose in the medium. However, mechanisms underlying nutrient-induced TORC1 activation remain poorly understood. By utilizing a TORC1 activation assay, we demonstrate that differential metabolism of glucose activates TORC1 through three distinct pathways in yeast. The first ‘canonical Rag GTPase-dependent pathway’ requires conversion of glucose to fructose 1,6-bisphosphate which activates TORC1 via the Rag GTPase heterodimer Gtr1 GTP /Gtr2 GDP . The second ‘non-canonical Rag GTPase-dependent pathway’ requires conversion of glucose to glucose 6-phosphate which activates TORC1 via Gtr1 GTP /Gtr2 GTP . The third ‘Rag GTPase-independent pathway’ requires complete glycolysis and vacuolar ATPase reassembly for TORC1 activation. Glucose-induced TORC1 activation can be uncoupled from glucose-induced AMPK inactivation. We have established a roadmap to deconstruct the link between glucose metabolism and TORC1 activation.