title: Chronological Lifespan in Yeast Is Dependent on the Accumulation of Storage Carbohydrates Mediated by Yak1, Mck1 and Rim15 Kinases.
abstract: Upon starvation for glucose or any other macronutrient, yeast cells exit from the mitotic cell cycle and acquire a set of characteristics that are specific to quiescent cells to ensure longevity. Little is known about the molecular determinants that orchestrate quiescence entry and lifespan extension. Using starvation-specific gene reporters, we screened a subset of the yeast deletion library representing the genes encoding 'signaling' proteins. Apart from the previously characterised Rim15, Mck1 and Yak1 kinases, the SNF1/AMPK complex, the cell wall integrity pathway and a number of cell cycle regulators were shown to be necessary for proper quiescence establishment and for extension of chronological lifespan (CLS), suggesting that entry into quiescence requires the integration of starvation signals transmitted via multiple signaling pathways. The CLS of these signaling mutants, and those of the single, double and triple mutants of RIM15, YAK1 and MCK1 correlates well with the amount of storage carbohydrates but poorly with transition-phase cell cycle status. Combined removal of the glycogen and trehalose biosynthetic genes, especially GSY2 and TPS1, nearly abolishes the accumulation of storage carbohydrates and severely reduces CLS. Concurrent overexpression of GSY2 and TSL1 or supplementation of trehalose to the growth medium ameliorates the severe CLS defects displayed by the signaling mutants (rim15Δyak1Δ or rim15Δmck1Δ). Furthermore, we reveal that the levels of intracellular reactive oxygen species are cooperatively controlled by Yak1, Rim15 and Mck1, and the three kinases mediate the TOR1-regulated accumulation of storage carbohydrates and CLS extension. Our data support the hypothesis that metabolic reprogramming to accumulate energy stores and the activation of anti-oxidant defence systems are coordinated by Yak1, Rim15 and Mck1 kinases to ensure quiescence entry and lifespan extension in yeast.
authors.affiliation: Cambridge Systems Biology Centre and Department of Biochemistry, University of Cambridge, Sanger Building, United Kingdom.
authors.forename: Lu
authors.identifier: http://orcid.org/0000-0002-1581-4133
authors.initials: L
authors.lastname: Cao
authors.affiliation: Cambridge Systems Biology Centre and Department of Biochemistry, University of Cambridge, Sanger Building, United Kingdom.
authors.forename: Yingzhi
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Cambridge Systems Biology Centre and Department of Biochemistry, University of Cambridge, Sanger Building, United Kingdom.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Quan
authors.affiliation: Cambridge Systems Biology Centre and Department of Biochemistry, University of Cambridge, Sanger Building, United Kingdom.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Cambridge Systems Biology Centre and Department of Biochemistry, University of Cambridge, Sanger Building, United Kingdom.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Oliver
authors.affiliation: Cambridge Systems Biology Centre and Department of Biochemistry, University of Cambridge, Sanger Building, United Kingdom.
authors.forename: Nianshu
authors.initials: N
authors.lastname: Zhang
mesh_terms: D050260:Carbohydrate Metabolism / Q000235:genetics; D002241:Carbohydrates / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D015966:Gene Expression Regulation, Fungal; D006003:Glycogen / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008136:Longevity / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014199:Trehalose / Q000096:biosynthesis / Q000235:genetics
chemical_list: D002241:Carbohydrates; D047908:Intracellular Signaling Peptides and Proteins; D029701:Saccharomyces cerevisiae Proteins; D006003:Glycogen; D014199:Trehalose; D011494:Protein Kinases; C410736:Rim15 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C062391:YAK1 protein, S cerevisiae; D038362:Glycogen Synthase Kinase 3; C068124:MCK1 protein, S cerevisiae