Crosstalk between the Tor and Gcn2 pathways in response to different stresses

Rødland, Gro Elise; Tvegård, Tonje; Boye, Erik; Grallert, Beáta

doi:10.4161/cc.27270

Cited by 17 publications

(20 citation statements)

References 41 publications

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“…Effectors downstream of TORC1 have been extensively characterised, including the AGC kinases Psk1, Sck1 and Sck2 that phosphorylate a variety of regulatory proteins to promote processes such as protein synthesis67. For example, a major regulator of protein translation, the translation initiation factor eIF2α89, can be phosphorylated by the Gcn2 kinase to inhibit translation; in nitrogen-rich conditions, Gcn2 is inactivated in a TORC1-dependent manner, thus providing a mechanism for TORC1 to promote translation in the presence of nutrients910.…”

mentioning

confidence: 99%

Genetic interactions and functional analyses of the fission yeast gsk3 and amk2 single and double mutants defective in TORC1-dependent processes

Rallis

Townsend

Bähler

2017

Sci Rep

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The Target of Rapamycin (TOR) signalling network plays important roles in aging and disease. The AMP-activated protein kinase (AMPK) and the Gsk3 kinase inhibit TOR during stress. We performed genetic interaction screens using synthetic genetic arrays (SGA) with gsk3 and amk2 as query mutants, the latter encoding the regulatory subunit of AMPK. We identified 69 negative and 82 positive common genetic interactors, with functions related to cellular growth and stress. The 120 gsk3-specific negative interactors included genes functioning in translation and ribosomes. The 215 amk2-specific negative interactors included genes functioning in chromatin silencing and DNA damage repair. Both amk2- and gsk3-specific interactors were enriched in phenotype categories related to abnormal cell size and shape. We also performed SGA screen with the amk2 gsk3 double mutant as a query. Mutants sensitive to 5-fluorouracil, an anticancer drug are under-represented within the 305 positive interactors specific for the amk2 gsk3 query. The triple-mutant SGA screen showed higher number of negative interactions than the double mutant SGA screens and uncovered additional genetic network information. These results reveal common and specialized roles of AMPK and Gsk3 in mediating TOR-dependent processes, indicating that AMPK and Gsk3 act in parallel to inhibit TOR function in fission yeast.

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confidence: 99%

Genetic interactions and functional analyses of the fission yeast gsk3 and amk2 single and double mutants defective in TORC1-dependent processes

Rallis

Townsend

Bähler

2017

Sci Rep

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“…Treating budding yeast with rapamycin, an inhibitor of the TOR kinases, leads to removal of an inhibitory phosphorylation on serine 577 of Gcn2, thought to reduce the threshold of uncharged tRNAs required for activation. However, this phosphorylation site is not conserved in fission yeast or in mammalian cells and even though inhibiting the Tor pathway can lead to increased Gcn2 activity also in fission yeast [ 9 , 44 ], the crosstalk between the two pathways depends on the particular stress applied [ 9 ]. In particular, Tor2 does not regulate eIF2α phosphorylation under a number of conditions, including UVC-irradiation and oxidative stress in fission yeast.…”

Section: Discussionmentioning

confidence: 99%

“…This role is conserved from yeast to human cells and the extent of conservation is such that the human Gcn2 can functionally replace the budding yeast Gcn2 [ 5 ]. Fission yeast has several eIF2α kinases and it is GCN2 that is activated in response to nutrient deprivation [ 6 – 9 ].…”

Section: Introductionmentioning

confidence: 99%

Activation of Gcn2 in response to different stresses

2017

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All organisms have evolved pathways to respond to different forms of cellular stress. The Gcn2 kinase is best known as a regulator of translation initiation in response to starvation for amino acids. Work in budding yeast has showed that the molecular mechanism of GCN2 activation involves the binding of uncharged tRNAs, which results in a conformational change and GCN2 activation. This pathway requires GCN1, which ensures delivery of the uncharged tRNA onto GCN2. However, Gcn2 is activated by a number of other stresses which do not obviously involve accumulation of uncharged tRNAs, raising the question how Gcn2 is activated under these conditions. Here we investigate the requirement for ongoing translation and tRNA binding for Gcn2 activation after different stresses in fission yeast. We find that mutating the tRNA-binding site on Gcn2 or deleting Gcn1 abolishes Gcn2 activation under all the investigated conditions. These results suggest that tRNA binding to Gcn2 is required for Gcn2 activation not only in response to starvation but also after UV irradiation and oxidative stress.

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“…These data clearly implicate FGF21 signaling in the metabolic adaptations to protein restriction, but whether brain amino acid sensing contributes to these responses remains to be clarified (Figure 1B). Interestingly, mTOR signaling interacts with GCN2 signaling (115, 116) and bidirectionally regulates FGF21 production (117), suggesting that multiple amino acid sensing pathways may orchestrate the overall metabolic and feeding responses to LP diets.…”

Section: Diets With Varying Protein Content: the Protein Leverage Hypmentioning

confidence: 99%

Central Amino Acid Sensing in the Control of Feeding Behavior

Heeley

Blouet

2016

Front. Endocrinol.

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Dietary protein quantity and quality greatly impact metabolic health via evolutionary-conserved mechanisms that ensure avoidance of amino acid imbalanced food sources, promote hyperphagia when dietary protein density is low, and conversely produce satiety when dietary protein density is high. Growing evidence supports the emerging concept of protein homeostasis in mammals, where protein intake is maintained within a tight range independently of energy intake to reach a target protein intake. The behavioral and neuroendocrine mechanisms underlying these adaptations are unclear. While peripheral factors are able to signal amino acid deficiency and abundance to the brain, the brain itself is exposed to and can detect changes in amino acid concentrations, and subsequently engages acute and chronic responses modulating feeding behavior and food preferences. In this review, we will examine the literature describing the mechanisms by which the brain senses changes in amino acids concentrations, and how these changes modulate feeding behavior.

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Crosstalk between the Tor and Gcn2 pathways in response to different stresses

Cited by 17 publications

References 41 publications

Genetic interactions and functional analyses of the fission yeast gsk3 and amk2 single and double mutants defective in TORC1-dependent processes

Genetic interactions and functional analyses of the fission yeast gsk3 and amk2 single and double mutants defective in TORC1-dependent processes

Activation of Gcn2 in response to different stresses

Central Amino Acid Sensing in the Control of Feeding Behavior

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