The target of rapamycin complex I (TORC1) regulates cell growth and metabolism in all eukaryotes. Previous studies have shown that nitrogen and amino acid signals activate TORC1 via three GTPases; Gtr1, Gtr2, and Rho1, and the SEA-associated Npr2/3 proteins. However, little is known about the way that other nutrient or stress signals are transmitted to TORC1. Here I present two studies identifying how, and at what level, glucose and other environmental stimuli act to tune TORC1 signaling. In the first study I show that the TORC1 pathway populates three additional stress/starvation states. First, in glucose starvation conditions, the AMP-activated protein kinase (AMPK/Snf1) and at least one other factor push the TORC1 pathway into an off state, in which Sch9-branch signaling and PP2A-branch signaling are both inhibited. The TORC1 pathway remains in the glucose starvation state even when cells are simultaneously starved for nitrogen and glucose or treated with rapamycin. Second, in osmotic stress, the MAPK Hog1/p38 drives the TORC1 pathway into a different state, in which Sch9 signaling and PP2A-branch signaling are inhibited, but PP2A-branch signaling can still be activated by nitrogen starvation. Third, in oxidative stress and heat stress, TORC1-Sch9 signaling is blocked while weak PP2A-branch signaling occurs. Together, the data show that the TORC1 pathway acts as an information-processing hub, activating different genes in different conditions to ensure that available energy is allocated to drive growth, amino acid synthesis, or a stress response, depending on the needs of the cell. In the second study I investigate further the observed hierarchy of TORC1 inputs. I show that glucose starvation triggers disassembly of TORC1, and movement of the key TORC1 component Kog1, to a single body near the edge of the vacuole. These events are driven by AMPK/Snf1-dependent phosphorylation of Kog1 at Serine 491/494 and two nearby prion-like motifs. Kog1-bodies then serve to increase the threshold for TORC1 activation in cells that have been starved for a significant period of time. Together, this data shows that Kog1-bodies create hysteresis (memory) in the TORC1 pathway and help ensure that cells remain committed to a quiescent state under suboptimal conditions.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/556430 |
| Date | January 2015 |
| Creators | Hughes Hallett, James |
| Contributors | Capaldi, Andrew, Capaldi, Andrew, Montfort, William, Nagy, Lisa, Serio, Tricia, Weinert, Ted |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Electronic Dissertation |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
Page generated in 0.0019 seconds