The target of rapamycin (TOR) is a conserved Ser/Thr kinase that controls cell growth by activating an array of anabolic processes including protein synthesis, transcription, and ribosome biogenesis, and by inhibiting catabolic processes such as mRNA degradation and autophagy. Control of autophagy by TOR occurs primarily at the induction step, and involves activation of the ATG1 kinase, a conserved component of the autophagic machinery. A substantial number of genes participating in autophagy have been originally identified in yeast. Most of these genes have mammalian homologues and many have apparent homologues in plants, indicating that autophagy is conserved among eukaryotes. The recent identification of TOR as a key element in cell growth control in plants and algae opens the way for future studies to investigate whether this signaling pathway may also control autophagy in photosynthetic organisms.

SUMMARY: TOR (target of rapamycin) is a phosphatidylinositol kinase-related protein kinase that controls cell growth in response to nutrients. Rapamycin is an immunosuppressive and anticancer drug that acts by inhibiting TOR. The modes of action of TOR and rapamycin are remarkably conserved from S. cerevisiae to humans. The current understanding of TOR and rapamycin is derived largely from studies with S. cerevisiae. In this review, we discuss the contributions made by S. cerevisiae to understanding rapamycin action and TOR function.

The essential, rapamycin-sensitive TOR kinases regulate a diverse set of cell growth-related readouts in response to nutrients. Thus, the yeast TOR proteins function as nutrient sensors, in particular as sensors of nitrogen and possibly carbon. However, the nutrient metabolite(s) that acts upstream of TOR is unknown. We investigated the role of glutamine, a preferred nitrogen source and a key intermediate in yeast nitrogen metabolism, as a possible regulator of TOR. We show that the glutamine synthetase inhibitor l -methionine sulfoximine (MSX) specifically provokes glutamine depletion in yeast cells. MSX-induced glutamine starvation caused nuclear localization and activation of the TOR-inhibited transcription factors GLN3, RTG1, and RTG3, all of which mediate glutamine synthesis. The MSX-induced nuclear localization of GLN3 required the TOR-controlled, type 2A-related phosphatase SIT4. Other TOR-controlled transcription factors, GAT1/NIL1, MSN2, MSN4, and an unknown factor involved in the expression of ribosomal protein genes, were not affected by glutamine starvation. These findings suggest that the TOR pathway senses glutamine. Furthermore, as glutamine starvation affects only a subset of TOR-controlled transcription factors, TOR appears to discriminate between different nutrient conditions to elicit a response appropriate to a given condition.