The budding yeast Saccharomyces cerevisiae grows far better at acidic than at neutral or alkaline pH. Consequently, even a modest alkalinization of the medium represents a stressful situation for this yeast. In the past few years, data generated by a combination of genome-wide techniques has demonstrated that adaptive responses of S. cerevisiae to high pH stress involves extensive gene remodeling as a result of the fast activation of a number of stress-related signaling pathways, such as the Rim101, the Wsc1-Pkc1-Slt2 MAP kinase, and the calcium-activated calcineurin pathways. Alkalinization of the environment also disturbs nutrient homeostasis, as deduced from its impact on iron/copper, phosphate, and glucose uptake/utilization pathways. In this review we will examine these responses, their possible interactions, and the role that they play in tolerance to high pH stress.
Get full access to this article
View all access options for this article.
References
1.
AlepuzP.M., CunninghamK.W., EstruchF.1997. Glucose repression affects ion homeostasis in yeast through the regulation of the stress-activated ENA1 gene. Mol Microbiol, 26:91–98.
2.
ArinoJ., RamosJ., SychrovaH.2010. Alkali metal cation transport and homeostasis in yeasts. Microbiol Mol Biol Rev, 74:95–120.
3.
BermejoC., RodriguezE., GarciaR., Rodriguez-PenaJ.M., Rodriguez de la ConcepcionM.L., RivasC.et al.2008. The sequential activation of the yeast HOG and SLT2 pathways is required for cell survival to cell wall stress. Mol Biol Cell, 19:1113–1124.
4.
CastrejonF., GomezA., SanzM., DuranA., RonceroC.2006. The RIM101 pathway contributes to yeast cell wall assembly and its function becomes essential in the absence of mitogen-activated protein kinase Slt2p. Eukaryot Cell, 5:507–517.
5.
CaustonH.C., RenB., KohS.S., HarbisonC.T., KaninE., JenningsE.G.et al.2001. Remodeling of yeast genome expression in response to environmental changes. Mol Biol Cell, 12:323–337.
6.
CrespoJ.L., DaichoK., UshimaruT., HallM.N.2001. The GATA transcription factors GLN3 and GAT1 link TOR to salt stress in Saccharomyces cerevisiae. J Biol Chem, 276:34441–34444.
7.
CyertM.S.2003. Calcineurin signaling in Saccharomyces cerevisiae: how yeast go crazy in response to stress. Biochem Biophys Res Commun, 311:1143–1150.
8.
DerisiJ.L., IyerV.R., BrownP.O.1997. Exploring the metabolic and genetic control of gene expression on a genomic scale. Science, 278:680–686.
9.
GarciaR., BermejoC., GrauC., PerezR., Rodriguez-PenaJ.M., FrancoisJ.et al.2004. The global transcriptional response to transient cell wall damage in Saccharomyces cerevisiae and its regulation by the cell integrity signaling pathway. J Biol Chem, 279:15183–15195.
10.
GarciaR., Rodriguez-PenaJ.M., BermejoC., NombelaC., ArroyoJ.2009. The high osmotic response and cell wall integrity pathways cooperate to regulate transcriptional responses to zymolyase-induced cell wall stress in Saccharomyces cerevisiae. J Biol Chem, 284:10901–10911.
11.
GarciadeblasB., RubioF., QuinteroF.J., BanuelosM.A., HaroR., Rodriguez-NavarroA.1993. Differential expression of two genes encoding isoforms of the ATPase involved in sodium efflux in Saccharomyces cerevisiae. Mol Gen Genet, 236:363–368.
12.
GiaeverG., ChuA.M., NiL., ConnellyC., RilesL., VeronneauS.et al.2002. Functional profiling of the Saccharomyces cerevisiae genome. Nature, 418:387–391.
13.
HayashiM., OhkuniK., YamashitaI.1998. Control of division arrest and entry into meiosis by extracellular alkalisation in Saccharomyces cerevisiae. Yeast, 14:905–913.
14.
HeathV.L., ShawS.L., RoyS., CyertM.S.2004. Hph1p and Hph2p, novel components of calcineurin-mediated stress responses in Saccharomyces cerevisiae. Eukaryot Cell, 3:695–704.
15.
HedbackerK., CarlsonM.2008. SNF1/AMPK pathways in yeast. Front Biosci, 13:2408–2420.
16.
HeylandJ., FuJ., BlankL.M.2009. Correlation between TCA cycle flux and glucose uptake rate during respiro-fermentative growth of Saccharomyces cerevisiae. Microbiology, 155:3827–3837.
17.
HongS.K., HanS.B., SnyderM., ChoiE.Y.1999. SHC1, a high pH inducible gene required for growth at alkaline pH in Saccharomyces cerevisiae. Biochem Biophys Res Commun, 255:116–122.
18.
HongS.P., CarlsonM.2007. Regulation of snf1 protein kinase in response to environmental stress. J Biol Chem, 282:16838–16845.
19.
KafadarK.A., CyertM.S.2004. Integration of stress responses: modulation of calcineurin signaling in Saccharomyces cerevisiae by protein kinase A. Eukaryot Cell, 3:1147–1153.
20.
LagorceA., HauserN.C., LabourdetteD., RodriguezC., Martin-YkenH., ArroyoJ.et al.2003. Genome-wide analysis of the response to cell wall mutations in the yeast Saccharomyces cerevisiae. J Biol Chem, 278:20345–20357.
21.
LambT.M., MitchellA.P.2003. The transcription factor Rim101p governs ion tolerance and cell differentiation by direct repression of the regulatory genes NRG1 and SMP1 in Saccharomyces cerevisiae. Mol Cell Biol, 23:677–686.
22.
LambT.M., XuW., DiamondA., MitchellA.P.2001. Alkaline response genes of Saccharomyces cerevisiae and their relationship to the RIM101 pathway. J Biol Chem, 276:1850–1856.
LiW., MitchellA.P.1997. Proteolytic activation of Rim1p, a positive regulator of yeast sporulation and invasive growth. Genetics, 145:63–73.
25.
Martinez-MunozG.A., KaneP.2008. Vacuolar and plasma membrane proton pumps collaborate to achieve cytosolic pH homeostasis in yeast. J Biol Chem, 283:20309–20319.
26.
MatheosD.P., KingsburyT.J., AhsanU.S., CunninghamK.W.1997. Tcn1p/Crz1p, a calcineurin-dependent transcription factor that differentially regulates gene expression in Saccharomyces cerevisiae. Genes Dev, 11:3445–3458.
27.
MendizabalI., RiosG., MuletJ.M., SerranoR., De LarrinoaI.F.1998. Yeast putative transcription factors involved in salt tolerance. FEBS Lett, 425:323–328.
28.
MendizabalI., Pascual-AhuirA., SerranoR., De LarrinoaI.F.2001. Promoter sequences regulated by the calcineurin-activated transcription factor Crz1 in the yeast ENA1 gene. Mol Genet Genomics, 265:801–811.
29.
MendozaI., RubioF., Rodriguez-NavarroA., PardoJ.M.1994. The protein phosphatase calcineurin is essential for NaCl tolerance of Saccharomyces cerevisiae. J Biol Chem, 269:8792–8796.
30.
MollapourM., PhelanJ.P., MillsonS.H., PiperP.W., CookeF.T.2006. Weak acid and alkali stress regulate phosphatidylinositol bisphosphate synthesis in Saccharomyces cerevisiae. Biochem J, 395:73–80.
31.
MouillonJ.M., PerssonB.L.2006. New aspects on phosphate sensing and signalling in Saccharomyces cerevisiae. FEMS Yeast Res, 6:171–176.
32.
NakamuraT., LiuY., HirataD., NambaH., HaradaS., HirokawaT.et al.1993. Protein phosphatase type 2B (calcineurin)-mediated, FK506-sensitive regulation of intracellular ions in yeast is an important determinant for adaptation to high salt stress conditions. EMBO J, 12:4063–4071.
33.
NelsonH., NelsonN.1990. Disruption of genes encoding subunits of yeast vacuolar H(+)-ATPase causes conditional lethality. Proc Natl Acad Sci USA, 87:3503–3507.
34.
PenalvaM.A., TilburnJ., BignellE., ArstH.N.Jr.2008. Ambient pH gene regulation in fungi: making connections. Trends Microbiol, 16:291–300.
35.
PerssonB.L., PeterssonJ., FristedtU., WeinanderR., BerheA., PattisonJ.1999. Phosphate permeases of Saccharomyces cerevisiae: structure, function and regulation. Biochim Biophys Acta, 1422:255–272.
36.
PlataraM., RuizA., SerranoR., PalominoA., MorenoF., ArinoJ.2006. The transcriptional response of the yeast Na+-ATPase ENA1 gene to alkaline stress involves three main signaling pathways. J Biol Chem, 281:36632–36642.
37.
PortilloF., MuletJ.M., SerranoR.2005. A role for the non-phosphorylated form of yeast Snf1: tolerance to toxic cations and activation of potassium transport. FEBS Lett, 579:512–516.
38.
RuizA., ArinoJ.2007. Function and regulation of the Saccharomyces cerevisiae ENA sodium ATPase system. Eukaryot Cell, 6:2175–2183.
39.
RuizA., SerranoR., ArinoJ.2008. Direct regulation of genes involved in glucose utilization by the calcium/calcineurin pathway. J Biol Chem, 283:13923–13933.
40.
SambadeM., AlbaM., SmardonA.M., WestR.W., KaneP.M.2005. A genomic screen for yeast vacuolar membrane ATPase mutants. Genetics, 170:1539–1551.
41.
SerranoR.1996. Salt tolerance in plants and microorganisms: toxicity targets and defense responses. Int Rev Cytol, 165:1–52.
42.
SerranoR.2006. Mecanismos de adaptación de Saccharomyces cerevisiae a la alcalinización ambiental. PhD Dissertation. Universitat Autònoma de Barcelona.
43.
SerranoR., Kielland-BrandtM.C., FinkG.R.1986. Yeast plasma membrane ATPase is essential for growth and has homology with (Na+ + K+), K+- and Ca2+-ATPases. Nature, 319:689–693.
44.
SerranoR., RuizA., BernalD., ChambersJ.R., ArinoJ.2002. The transcriptional response to alkaline pH in Saccharomyces cerevisiae: evidence for calcium-mediated signalling. Mol Microbiol, 46:1319–1333.
45.
SerranoR., BernalD., SimonE., ArinoJ.2004. Copper and iron are the limiting factors for growth of the yeast Saccharomyces cerevisiae in an alkaline environment. J Biol Chem, 279:19698–19704.
46.
SerranoR., MartinH., CasamayorA., ArinoJ.2006. Signaling alkaline pH stress in the yeast Saccharomyces cerevisiae through the Wsc1 cell surface sensor and the Slt2 MAPK pathway. J Biol Chem, 281:39785–39795.
47.
StathopoulosA.M., CyertM.S.1997. Calcineurin acts through the CRZ1/TCN1-encoded transcription factor to regulate gene expression in yeast. Genes Dev, 11:3432–3444.
48.
StrahlT., ThornerJ.2007. Synthesis and function of membrane phosphoinositides in budding yeast, Saccharomyces cerevisiae. Biochim Biophys Acta, 1771:353–404.
49.
SuS.S.Y., MitchellA.P.1993. Identification of functionally related genes that stimulate early meiotic gene-expression in yeast. Genetics, 133:67–77.
50.
TretonB., Blanchin-RolandS., LambertM., LepingleA., GaillardinC.2000. Ambient pH signalling in ascomycetous yeasts involves homologues of the Aspergillus nidulans genes palF and paIH. Mol Gen Genet, 263:505–513.
51.
Van der RestM.E., KammingaA.H., NakanoA., AnrakuY., PoolmanB., KoningsW.N.1995. The plasma membrane of Saccharomyces cerevisiae: structure, function, and biogenesis. Microbiol Rev, 59:304–322.
52.
ViladevallL., SerranoR., RuizA., DomenechG., GiraldoJ., BarceloA.et al.2004. Characterization of the calcium-mediated response to alkaline stress in Saccharomyces cerevisiae. J Biol Chem, 279:43614–43624.
53.
YazawaH., IwahashiH., KamisakaY., KimuraK., UemuraH.2009. Production of polyunsaturated fatty acids in yeast Saccharomyces cerevisiae and its relation to alkaline pH tolerance. Yeast, 26:167–184.
54.
YeT., Garcia-SalcedoR., RamosJ., HohmannS.2006. Gis4, a new component of the ion homeostasis system in the yeast Saccharomyces cerevisiae. Eukaryot Cell, 5:1611–1621.
55.
YoshimotoH., SaltsmanK., GaschA.P., LiH.X., OgawaN., BotsteinD.et al.2002. Genome-wide analysis of gene expression regulated by the calcineurin/Crz1p signaling pathway in Saccharomyces cerevisiae. J Biol Chem, 277:31079–31088.
