State Transitions in the TORC1 Signaling Pathway and Information Processing in <i>Saccharomyces cerevisiae</i>

Hallett, James E. Hughes; Luo, Xiangxia; Capaldi, Andrew P.

doi:10.1534/genetics.114.168369

Cited by 118 publications

(154 citation statements)

References 77 publications

(144 reference statements)

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“…Evidence suggests that TORC1 and Snf1p/AMPK converge in the regulation of fatty acid metabolism and other outputs independently (57). A recent work provided strong evidence that Snf1p/AMPK participates as a possible upstream regulator of the TORC1 pathway under glucose-limiting conditions (58).…”

Section: Discussionmentioning

confidence: 99%

TORC1 Inhibition Induces Lipid Droplet Replenishment in Yeast

Madeira

Masuda

Maya‐Monteiro

et al. 2015

Molecular and Cellular Biology

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bLipid droplets (LDs) are intracellular structures that regulate neutral lipid homeostasis. In mammals, LD synthesis is inhibited by rapamycin, a known inhibitor of the mTORC1 pathway. In Saccharomyces cerevisiae, LD dynamics are modulated by the growth phase; however, the regulatory pathways involved are unknown. Therefore, we decided to study the role of the TORC1 pathway on LD metabolism in S. cerevisiae. Interestingly, rapamycin treatment resulted in a fast LD replenishment and growth inhibition. The discovery that osmotic stress (1 M sorbitol) also induced LD synthesis but not growth inhibition suggested that the induction of LDs in yeast is not a secondary response to reduced growth. The induction of LDs by rapamycin was due to increased triacylglycerol but not sterol ester synthesis. Induction was dependent on the TOR downstream effectors, the PP2A-related phosphatase Sit4p and the regulatory protein Tap42p. The TORC1-controlled transcriptional activators Gln3p, Gat1p, Rtg1p, and Rtg3p, but not Msn2p and Msn4p, were required for full induction of LDs by rapamycin. Furthermore, we show that the deletion of Gln3p and Gat1p transcription factors, which are activated in response to nitrogen availability, led to abnormal LD dynamics. These results reveal that the TORC1 pathway is involved in neutral lipid homeostasis in yeast. Lipid droplets (LDs) are intracellular structures formed by a core of neutral lipids, mainly triacylglycerols (TAG) and sterol esters (SE), which are delimited by a phospholipid monolayer embedded with proteins primarily related to lipid metabolism (1-3). At first, LDs were believed to be mere neutral lipid deposits, but later it became clear that LDs play other important roles in cellular physiology. The main function of LDs is to maintain cellular lipid homeostasis (4, 5), and it was shown that defects in the mobilization of neutral lipids from LDs are related to type 2 diabetes, inflammation, neurodegenerative disorders, and cancer (6-8). In addition to their importance in health, LDs also are studied in oleaginous yeast for their exploitation as cellular oil factories for biofuel production (9).Although the metabolic steps of LD biogenesis are well known, the signals that govern LD dynamics are not clear yet. Because the signaling pathways are well conserved between yeast and mammals, Saccharomyces cerevisiae has been a model for studying LD dynamics. In S. cerevisiae, LDs follow a particular dynamic tightly linked to the growth phase and to the nutritional status of the cell (10, 11). When quiescent yeast cells encounter a rich medium containing glucose, cells must exit G 0 in order to start duplication and cell growth (12). This start demands a large amount of sterols and fatty acids, leading to the strong mobilization of the neutral lipids stored in LDs. As a result, LDs are diminished in number and in size (10). After this strong lipolytic phase, yeast cells shift to a lipogenic phase to replenish the levels of LDs, reaching its maximum at early stationary phase (10, 11).The regu...

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Section: Discussionmentioning

confidence: 99%

TORC1 Inhibition Induces Lipid Droplet Replenishment in Yeast

Madeira

Masuda

Maya‐Monteiro

et al. 2015

Molecular and Cellular Biology

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“…However, Npr2 and Npr3 have little effect on TORC1 signaling under conditions of glucose starvation or stress (Hughes Hallett (296) Sec13 (322) β-propeller 2-296 1-322 Devos et al, 2004Devos et al, et al, 2014Neklesa and Davis, 2009). Taken together, these data suggest that Npr2-and Npr3-mediated signaling through TORC1 diverts energy from protein biosynthesis towards the production of amino acids and other metabolites (Hughes Hallett et al, 2014).…”

Section: Box 2 Sea/gator Homologs In Other Organismsmentioning

confidence: 99%

SEA you later alli-GATOR – a dynamic regulator of the TORC1 stress response pathway

Dokudovskaya

Rout

2015

Journal of Cell Science

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Cells constantly adapt to various environmental changes and stresses. The way in which nutrient and stress levels in a cell feed back to control metabolism and growth are, unsurprisingly, extremely complex, as responding with great sensitivity and speed to the 'feast or famine, slack or stress' status of its environment is a central goal for any organism. The highly conserved target of rapamycin complex 1 (TORC1) controls eukaryotic cell growth and response to a variety of signals, including nutrients, hormones and stresses, and plays the key role in the regulation of autophagy. A lot of attention has been paid recently to the factors in this pathway functioning upstream of TORC1. In this Commentary, we focus on a major, newly discovered upstream regulator of TORC1 -the multiprotein SEA complex, also known as GATOR. We describe the structural and functional features of the yeast complex and its mammalian homolog, and their involvement in the regulation of the TORC1 pathway and TORC1-independent processes. We will also provide an overview of the consequences of GATOR deregulation in cancer and other diseases.

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“…As proposed previously (28), it seems likely that some additional growth-related targets of Reg2-Glc7 could actually be phosphorylation substrates of Snf1 itself. In this regard, it has been recently reported that Snf1 phosphorylates and negatively regulates adenylate cyclase (58) and that it also inhibits the progrowth TORC1 pathway in response to glucose starvation (59,60), raising the possibility that Reg2-Glc7 might target components of the Ras-cAMP-PKA and/or TORC1 pathway. It certainly also remains possible that some relevant targets of Reg2-Glc7 could lie outside the Snf1 pathway.…”

Section: Discussionmentioning

confidence: 99%

Springing into Action: Reg2 Negatively Regulates Snf1 Protein Kinase and Facilitates Recovery from Prolonged Glucose Starvation in Saccharomyces cerevisiae

Maziarz

Shevade

Barrett

et al. 2016

Appl Environ Microbiol

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Glucose is the preferred carbon source for the yeast Saccharomyces cerevisiae. Glucose limitation activates Snf1 protein kinase, a key regulator of energy homeostasis that promotes utilization of alternative carbon sources and enforces energy conservation. Snf1 activation requires phosphorylation of its T-loop threonine (Thr210) by upstream kinases. When glucose is abundant, Snf1 is inhibited by Thr210 dephosphorylation. This involves the function of the type 1 protein phosphatase Glc7, which is targeted to Snf1 by a regulatory subunit, Reg1. The reg1 mutation causes increased Snf1 activity and mimics various aspects of glucose limitation, including slower growth. Reg2 is another Glc7 regulatory subunit encoded by a paralogous gene, REG2. Previous evidence indicated that the reg2 mutation exacerbates the Snf1-dependent slow-growth phenotype caused by reg1, suggesting a link between Reg2 and Snf1. Here, we explore this link in more detail and present evidence that Reg2 contributes to Snf1 Thr210 dephosphorylation. Consistent with this role, Reg2 interacts with wild-type Snf1 but not with nonphosphorylatable Snf1-T210A. Reg2 accumulation increases in a Snf1-dependent manner during prolonged glucose deprivation, and glucose-starved cells lacking Reg2 exhibit delayed Snf1 Thr210 dephosphorylation and slower growth recovery upon glucose replenishment. Accordingly, cells lacking Reg2 are outcompeted by wild-type cells in the course of several glucose starvation/replenishment cycles. Collectively, our results support a model in which Reg2-Glc7 contributes to the negative control of Snf1 in response to glucose refeeding after prolonged starvation. The competitive growth advantage provided by Reg2 underscores the evolutionary significance of this paralog for S. cerevisiae. IMPORTANCEThe ability of microorganisms to respond to stress is essential for their survival. However, rapid recovery from stress could be equally crucial in competitive environments. Therefore, a wise stress response program should prepare cells for quick recovery upon reexposure to favorable conditions. Glucose is the preferred carbon source for the yeast S. cerevisiae. Glucose depletion activates the stress response protein kinase Snf1, which functions to limit energy-consuming processes, such as growth. We show that prolonged glucose deprivation also leads to Snf1-dependent accumulation of Reg2 and that this protein helps to inhibit Snf1 and to accelerate growth recovery upon glucose replenishment. Cells lacking Reg2 are readily outcompeted by wild-type cells during glucose depletion/replenishment cycles. Thus, while prolonged glucose deprivation might seem to put yeast cells "on their knees," concomitant accumulation of Reg2 helps configure the cells into a "sprinter's crouch start position" to spring into action once glucose becomes available. Glucose is a preferred source of carbon and energy for a wide variety of microorganisms. Although the yeast Saccharomyces cerevisiae can exist in many different environments, it is particularly know...

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State Transitions in the TORC1 Signaling Pathway and Information Processing in Saccharomyces cerevisiae

Cited by 118 publications

References 77 publications

TORC1 Inhibition Induces Lipid Droplet Replenishment in Yeast

TORC1 Inhibition Induces Lipid Droplet Replenishment in Yeast

SEA you later alli-GATOR – a dynamic regulator of the TORC1 stress response pathway

Springing into Action: Reg2 Negatively Regulates Snf1 Protein Kinase and Facilitates Recovery from Prolonged Glucose Starvation in Saccharomyces cerevisiae

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