Abstract
In response to various environmental stimuli and stressors, the budding yeast Saccharomyces cerevisiae can initiate a striking morphological transition from its classic growth mode as isolated single cells to a filamentous form in which elongated cells remain connected post-cytokinesis in multi-cellular pseudohyphae. The formation of pseudohyphal filaments is regulated through an expansive signaling network, encompassing well studied and highly conserved pathways enabling changes in cell polarity, budding, cytoskeletal organization, and cell adhesion; however, changes in metabolite levels underlying the pseudohyphal growth transition are less well understood. We have recently identified a function for second messenger inositol polyphosphates (InsPs) in regulating pseudohyphal growth. InsPs are formed through the cleavage of membrane-bound phosphatidylinositol 4,5-bisphosphate (PIP2), and these soluble compounds are now being appreciated as important regulators of diverse processes, from phosphate homeostasis to cell migration. We find that kinases in the InsP pathway are required for wild-type pseudohyphal growth, and that InsP species exhibit characteristic profiles under conditions promoting filamentation. Ratios of the doubly phosphorylated InsP7 isoforms 5PP-InsP5 to 1PP-InsP5 are elevated in mutants exhibiting exaggerated pseudohyphal growth. Interestingly, S. cerevisiae mutants deleted of the mitogen-activated protein kinases (MAPKs) Kss1p or Fus3p or the AMP-activated kinase (AMPK) family member Snf1p display mutant InsP profiles, suggesting that these signaling pathways may contribute to the regulatory mechanism controlling InsP levels. Consequently, analyses of yeast pseudohyphal growth may be informative in identifying mechanisms regulating InsPs, while indicating a new function for these conserved second messengers in modulating cell stress responses and morphogenesis.
Similar content being viewed by others
References
Azevedo C, Burton A, Ruiz-Mateos E, Marsh M, Saiardi A (2009) Inositol pyrophosphate mediated pyrophosphorylation of AP3B1 regulates HIV-1 Gag release. Proc Natl Acad Sci USA 106:21161–21166. https://doi.org/10.1073/pnas.0909176106
Bao MZ, Schwartz MA, Cantin GT, Yates JR, Madhani H (2004) Pheromone-dependent destruction of the Tec1 transcription factor is required for MAP kinase signaling specificity in yeast. Cell 119:991–1000
Bardwell L, Cook JG, Voora D, Baggott DM, Martinez AR, Thorner J (1998) Repression of yeast Ste12 transcription factor by direct binding of unphosphorylated Kss1 MAPK and its regulation by the Ste7 MEK. Genes Dev 12:2887–2898
Bennett M, Onnebo SM, Azevedo C, Saiardi A (2006) Inositol pyrophosphates: metabolism and signaling. Cell Mol Life Sci 63:552–564. https://doi.org/10.1007/s00018-005-5446-z
Bhandari R, Saiardi A, Ahmadibeni Y, Snowman AM, Resnick AC, Kristiansen TZ, Molina H, Pandey A, Werner JK Jr, Juluri KR, Xu Y, Prestwich GD, Parang K, Snyder SH (2007) Protein pyrophosphorylation by inositol pyrophosphates is a posttranslational event. Proc Natl Acad Sci USA 104:15305–15310. https://doi.org/10.1073/pnas.0707338104
Boeckstaens M, Andre B, Marini AM (2008) Distinct transport mechanisms in yeast ammonium transport/sensor proteins of the Mep/Amt/Rh family and impact on filamentation. J Biol Chem 283:21362–21370. https://doi.org/10.1074/jbc.M801467200
Braun BR, Johnson AD (1997) Control of filament formation in Candida albicans by the transcriptional repressor TUP1. Science 277:105–109
Braus GH, Grundmann O, Bruckner S, Mosch HU (2003) Amino acid starvation and Gcn4p regulate adhesive growth and FLO11 gene expression in Saccharomyces cerevisiae. Mol Biol Cell 14:4272–4284. https://doi.org/10.1091/mbc.e03-01-0042
Chakraborty A, Koldobskiy MA, Bello NT, Maxwell M, Potter JJ, Juluri KR, Maag D, Kim S, Huang AS, Dailey MJ, Saleh M, Snowman AM, Moran TH, Mezey E, Snyder SH (2010) Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain. Cell 143:897–910. https://doi.org/10.1016/j.cell.2010.11.032
Chakraborty A, Kim S, Snyder SH (2011) Inositol pyrophosphates as mammalian cell signals. Sci Signal 4:re1. https://doi.org/10.1126/scisignal.2001958
Chanduri M, Rai A, Malla AB, Wu M, Fiedler D, Mallik R, Bhandari R (2016) Inositol hexakisphosphate kinase 1 (IP6K1) activity is required for cytoplasmic dynein-driven transport. Biochem J 473:3031–3047. https://doi.org/10.1042/BCJ20160610
Chen H, Fink GR (2006) Feedback control of morphogenesis in fungi by aromatic alcohols. Genes Dev 20:1150–1161. https://doi.org/10.1101/gad.1411806
Cook JG, Bardwell L, Kron SJ, Thorner J (1996) Two novel targets of the MAP kinase Kss1 are negative regulators of invasive growth in the yeast Saccharomyces cerevisiae. Genes Dev 10:2831–2848
Cook JG, Bardwell L, Thorner J (1997) Inhibitory and activating functions forMAPK Kss1 in the S. cerevisiae filamentous growth signalling pathway. Nature 390:85–88
Cullen PJ, Sprague GF (2000) Glucose depletion causes haploid invasive growth in yeast. Proc Natl Acad Sci USA 97:13461–13463
Cullen PJ, Sprague GF Jr (2002) The roles of bud-site-selection proteins during haploid invasive growth in yeast. Mol Biol Cell 13:2990–3004. https://doi.org/10.1091/mbc.E02-03-0151
Cullen PJ, Sprague GF Jr (2012) The regulation of filamentous growth in yeast. Genetics 190:23–49. https://doi.org/10.1534/genetics.111.127456
Dubois E, Scherens B, Vierendeels F, Ho MM, Messenguy F, Shears SB (2002) In Saccharomyces cerevisiae, the inositol polyphosphate kinase activity of Kcs1p is required for resistance to salt stress, cell wall integrity, and vacuolar morphogenesis. J Biol Chem 277:23755–23763. https://doi.org/10.1074/jbc.M202206200
Erdman S, Lin L, Malczynski M, Snyder M (1998) Pheromone-regulated genes required for yeast mating differentiation. J Cell Biol 140:461–483
Evangelista M, Blundell K, Longtine MS, Chow CJ, Adames N, Pringle JR, Peter M, Boone C (1997) Bni1p, a yeast formin linking cdc42p and the actin cytoskeleton during polarized morphogenesis. Science 276:118–122
Fidalgo M, Barrales RR, Ibeas JI, Jimenez J (2006) Adaptive evolution by mutations in the FLO11 gene. Proc Natl Acad Sci USA 103:11228–11233. https://doi.org/10.1073/pnas.0601713103
Flick JS, Thorner J (1993) Genetic and biochemical characterization of a phosphatidylinositol-specific phospholipase C in Saccharomyces cerevisiae. Mol Cell Biol 13:5861–5876
Gibney PA, Lu C, Caudy AA, Hess DC, Botstein D (2013) Yeast metabolic and signaling genes are required for heat-shock survival and have little overlap with the heat-induced genes. Proc Natl Acad Sci USA 110:E4393–E4402. https://doi.org/10.1073/pnas.1318100110
Gimeno CJ, Ljungdahl PO, Styles CA, Fink GR (1992) Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth: regulation by starvation and RAS. Cell 68:1077–1090
Gladfelter AS, Kozubowski L, Zyla TR, Lew DJ (2005) Interplay between septin organization, cell cycle and cell shape in yeast. J Cell Sci 118:1617–1628. https://doi.org/10.1242/jcs.02286
Guldener U, Koehler GJ, Haussmann C, Bacher A, Kricke J, Becher D, Hegemann JH (2004) Characterization of the Saccharomyces cerevisiae Fol1 protein: starvation for C1 carrier induces pseudohyphal growth. Mol Biol Cell 15:3811–3828. https://doi.org/10.1091/mbc.e03-09-0680
Guo B, Styles CA, Feng Q, Fink G (2000) A Saccharomyces gene family involved in invasive growth, cell-cell adhesion, and mating. Proc Natl Acad Sci USA 97:12158–12163
Halme A, Bumgarner S, Styles CA, Fink GR (2004) Genetic and epigenetic regulation of the FLO gene family generates cell-surface variation in yeast. Cell 116:405–415
Harkins HA, Page N, Schenkman LR, De Virgilio C, Shaw S, Bussey H, Pringle JR (2001) Bud8p and Bud9p, proteins that may mark the sites for bipolar budding in yeast. Mol Biol Cell 12:2497–2518. https://doi.org/10.1091/mbc.12.8.2497
Hatch AJ, York JD (2010) SnapShot: inositol phosphates. Cell 143:1030–1030.e1. https://doi.org/10.1016/j.cell.2010.11.045
Iyer RS, Bhat PJ (2017) KRH1 and KRH2 are functionally non-redundant in signaling for pseudohyphal differentiation in Saccharomyces cerevisiae. Curr Genet 63:851–859. https://doi.org/10.1007/s00294-017-0684-9
Jin R, Dobry CJ, McCown PJ, Kumar A (2008) Large-scale analysis of yeast filamentous growth by systematic gene disruption and overexpression. Mol Biol Cell 19:284–296
Kang H, Lew DJ (2017) How do cells know what shape they are? Curr Genet 63:75–77. https://doi.org/10.1007/s00294-016-0623-1
Karunanithi S, Vadaie N, Chavel CA, Birkaya B, Joshi J, Grell L, Cullen PJ (2010) Shedding of the mucin-like flocculin Flo11p reveals a new aspect of fungal adhesion regulation. Curr Biol 20:1389–1395
Kim S, Kim SF, Maag D, Maxwell MJ, Resnick AC, Juluri KR, Chakraborty A, Koldobskiy MA, Cha SH, Barrow R, Snowman AM, Snyder SH (2011) Amino acid signaling to mTOR mediated by inositol polyphosphate multikinase. Cell Metab 13:215–221. https://doi.org/10.1016/j.cmet.2011.01.007
Kron SJ, Styles CA, Fink GR (1994) Symmetric cell division in pseudohyphae of the yeast Saccharomyces cerevisiae. Mol Biol Cell 5:1003–1022
Kuchin S, Vyas VK, Carlson M (2002) Snf1 protein kinase and the repressors Nrg1 and Nrg2 regulate FLO11, haploid invasive growth, and diploid pseudohyphal differentiation. Mol Cell Biol 22:3994–4000
Lambrechts MG, Bauer FF, Marmur J, Pretorius IS (1996) Muc1, a mucin-like protein that is regulated by Mss10, is critical for pseudohyphal differentiation in yeast. Proc Natl Acad Sci USA 93:8419–8424
Lee YS, Mulugu S, York JD, O’Shea EK (2007) Regulation of a cyclin-CDK-CDK inhibitor complex by inositol pyrophosphates. Science 316:109–112. https://doi.org/10.1126/science.1139080
Lev S, Li C, Desmarini D, Saiardi A, Fewings NL, Schibeci SD, Sharma R, Sorrell TC, Djordjevic JT (2015) Fungal inositol pyrophosphate IP7 is crucial for metabolic adaptation to the host environment and pathogenicity. MBio 6:e00531–e00515. https://doi.org/10.1128/mBio.00531-15
Liu H, Styles CA, Fink GR (1993) Elements of the yeast pheromone response pathway required for filamentous growth of diploids. Science 262:1741–1744
Lo WS, Dranginis AM (1996) FLO11, a yeast gene related to the STA genes, encodes a novel cell surface flocculin. J Bacteriol 178:7144–7151
Lo WS, Dranginis AM (1998) The cell surface flocculin Flo11 is required for pseudohyphae formation and invasion by Saccharomyces cerevisiae. Mol Biol Cell 9:161–171
Lo HJ, Kohler J, DiDomenico B, Loebenberg D, Cacciapuoti A, Fink GR (1997) Nonfilamentous C. albicans mutants are avirulent. Cell 90:939–949
Lorenz MC, Cutler NS, Heitman J (2000) Characterization of alcohol-induced filamentous growth in Saccharomyces cerevisiae. Mol Biol Cell 11:183–199
Madhani HD, Fink GR (1997) Combinatorial control required for the specificity of yeast MAPK signaling. Science 275:1314–1317
Madhani HD, Styles CA, Fink GR (1997) MAP kinases with distinct inhibitory functions impart signaling specificity during yeast differentiation. Cell 91:673–684
Michell RH, Kirk CJ, Jones LM, Downes CP, Creba JA (1981) The stimulation of inositol lipid metabolism that accompanies calcium mobilization in stimulated cells: defined characteristics and unanswered questions. Philos Trans R Soc Lond B Biol Sci 296:123–138
Mitchell AP (1998) Dimorphism and virulence in Candida albicans. Curr Opin Microbiol 1:687–692
Monserrate JP, York JD (2010) Inositol phosphate synthesis and the nuclear processes they affect. Curr Opin Cell Biol 22:365–373. https://doi.org/10.1016/j.ceb.2010.03.006
Mosch HU, Roberts RL, Fink GR (1996) Ras2 signals via the Cdc42/Ste20/mitogen-activated protein kinase module to induce filamentous growth in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 93:5352–5356
Mulugu S, Bai W, Fridy PC, Bastidas RJ, Otto JC, Dollins DE, Haystead TA, Ribeiro AA, York JD (2007) A conserved family of enzymes that phosphorylate inositol hexakisphosphate. Science 316:106–109. https://doi.org/10.1126/science.1139099
Norman KL, Shively CA, De La Rocha AJ, Mutlu N, Basu S, Cullen PJ, Kumar A (2018) Inositol polyphosphates regulate and predict yeast pseudohyphal growth phenotypes. PLoS Genet 14:e1007493. https://doi.org/10.1371/journal.pgen.1007493
Pan X, Heitman J (1999) Cyclic AMP-dependent protein kinase regulates pseudohyphal differentiation in Saccharomyces cerevisiae. Mol Cell Biol 19:4874–4887
Pohlmann J, Fleig U (2010) Asp1, a conserved 1/3 inositol polyphosphate kinase, regulates the dimorphic switch in Schizosaccharomyces pombe. Mol Cell Biol 30:4535–4547. https://doi.org/10.1128/MCB.00472-10
Pohlmann J, Risse C, Seidel C, Pohlmann T, Jakopec V, Walla E, Ramrath P, Takeshita N, Baumann S, Feldbrugge M, Fischer R, Fleig U (2014) The Vip1 inositol polyphosphate kinase family regulates polarized growth and modulates the microtubule cytoskeleton in fungi. PLoS Genet 10:e1004586. https://doi.org/10.1371/journal.pgen.1004586
Rao RP, Hunter A, Kashpur O, Normanly J (2010) Aberrant synthesis of indole-3-acetic acid in Saccharomyces cerevisiae triggers morphogenic transition, a virulence trait of pathogenic fungi. Genetics 185:211–220. https://doi.org/10.1534/genetics.109.112854
Rao MJ, Srinivasan M, Rajasekharan R (2018) Cell size is regulated by phospholipids and not by storage lipids in Saccharomyces cerevisiae. Curr Genet. https://doi.org/10.1007/s00294-018-0821-0
Roberts RL, Fink GR (1994) Elements of a single MAP kinase cascade in Saccharomyces cerevisiae mediate two developmental programs in the same cell type: mating and invasive growth. Genes Dev 8:2974–2985
Robertson LS, Fink GR (1998) The three yeast A kinases have specific signaling functions in pseudohyphal growth. Proc Natl Acad Sci USA 95:13783–13787
Rupp S, Summers E, Lo HJ, Madhani H, Fink G (1999) MAP kinase and cAMP filamentation signaling pathways converge on the unusually large promoter of the yeast FLO11 gene. EMBO J 18:1257–1269
Ryan O, Shapiro RS, Kurat CF, Mayhew D, Baryshnikova A, Chin B, Lin ZY, Cox MJ, Vizeacoumar F, Cheung D, Bahr S, Tsui K, Tebbji F, Sellam A, Istel F, Schwarzmuller T, Reynolds TB, Kuchler K, Gifford DK, Whiteway M, Giaever G, Nislow C, Costanzo M, Gingras AC, Mitra RD, Andrews B, Fink GR, Cowen LE, Boone C (2012) Global gene deletion analysis exploring yeast filamentous growth. Science 337:1353–1356. https://doi.org/10.1126/science.1224339
Saiardi A (2016) Protein pyrophosphorylation: moving forward. Biochem J 473:3765–3768. https://doi.org/10.1042/BCJ20160710C
Saiardi A, Erdjument-Bromage H, Snowman AM, Tempst P, Snyder SH (1999) Synthesis of diphosphoinositol pentakisphosphate by a newly identified family of higher inositol polyphosphate kinases. Curr Biol 9:1323–1326
Saiardi A, Resnick AC, Snowman AM, Wendland B, Snyder SH (2005) Inositol pyrophosphates regulate cell death and telomere length through phosphoinositide 3-kinase-related protein kinases. Proc Natl Acad Sci USA 102:1911–1914. https://doi.org/10.1073/pnas.0409322102
Shears SB, Ganapathi SB, Gokhale NA, Schenk TM, Wang H, Weaver JD, Zaremba A, Zhou Y (2012) Defining signal transduction by inositol phosphates. Subcell Biochem 59:389–412. https://doi.org/10.1007/978-94-007-3015-1_13
Shively CA, Eckwahl MJ, Dobry CJ, Mellacheruvu D, Nesvizhskii A, Kumar A (2013) Genetic networks inducing invasive growth in Saccharomyces cerevisiae identified through systematic genome-wide overexpression. Genetics 193:1297–1310. https://doi.org/10.1534/genetics.112.147876
Shively CA, Kweon HK, Norman KL, Mellacheruvu D, Xu T, Sheidy DT, Dobry CJ, Sabath I, Cosky EE, Tran EJ, Nesvizhskii A, Andrews PC, Kumar A (2015) Large-scale analysis of kinase signaling in yeast pseudohyphal development identifies regulation of ribonucleoprotein granules. PLoS Genet 11:e1005564. https://doi.org/10.1371/journal.pgen.1005564
Simpson-Lavy K, Kupiec M (2018) A reversible liquid drop aggregation controls glucose response in yeast. Curr Genet 64:785–788. https://doi.org/10.1007/s00294-018-0805-0
Steidle EA, Chong LS, Wu M, Crooke E, Fiedler D, Resnick AC, Rolfes RJ (2016) A novel inositol pyrophosphate phosphatase in Saccharomyces cerevisiae: Siw14 protein selectively cleaves the beta-phosphate from 5-diphosphoinositol pentakisphosphate (5PP-Ip5). J Biol Chem 291:6772–6783. https://doi.org/10.1074/jbc.M116.714907
Swaney DL, Beltrao P, Starita L, Guo A, Rush J, Fields S, Krogan NJ, Villen J (2013) Global analysis of phosphorylation and ubiquitylation cross-talk in protein degradation. Nat Methods 10:676–682. https://doi.org/10.1038/nmeth.2519
Szijgyarto Z, Garedew A, Azevedo C, Saiardi A (2011) Influence of inositol pyrophosphates on cellular energy dynamics. Science 334:802–805. https://doi.org/10.1126/science.1211908
Thota SG, Unnikannan CP, Thampatty SR, Manorama R, Bhandari R (2015) Inositol pyrophosphates regulate RNA polymerase I-mediated rRNA transcription in Saccharomyces cerevisiae. Biochem J 466:105–114. https://doi.org/10.1042/BJ20140798
Venters BJ, Wachi S, Mavrich TN, Andersen BE, Jena P, Sinnamon AJ, Jain P, Rolleri NS, Jiang C, Hemeryck-Walsh C, Pugh BF (2011) A comprehensive genomic binding map of gene and chromatin regulatory proteins in Saccharomyces. Mol Cell 41:480–492. https://doi.org/10.1016/j.molcel.2011.01.015
Verstrepen KJ, Jansen A, Lewitter F, Fink GR (2005) Intragenic tandem repeats generate functional variability. Nat Genet 37:986–990. https://doi.org/10.1038/ng1618
Vyas VK, Kuchin S, Berkey CD, Carlson M (2003) Snf1 kinases with different beta-subunit isoforms play distinct roles in regulating haploid invasive growth. Mol Cell Biol 23:1341–1348
Wickner RB, Kelly AC, Bezsonov EE, Edskes HK (2017) [PSI+] prion propagation is controlled by inositol polyphosphates. Proc Natl Acad Sci USA 114:E8402–E8410. https://doi.org/10.1073/pnas.1714361114
Wickner RB, Edskes HK, Bezsonov EE, Son M, Ducatez M (2018) Prion propagation and inositol polyphosphates. Curr Genet 64:571–574. https://doi.org/10.1007/s00294-017-0788-2
Wild R, Gerasimaite R, Jung JY, Truffault V, Pavlovic I, Schmidt A, Saiardi A, Jessen HJ, Poirier Y, Hothorn M, Mayer A (2016) Control of eukaryotic phosphate homeostasis by inositol polyphosphate sensor domains. Science 352:986–990. https://doi.org/10.1126/science.aad9858
Worley J, Luo X, Capaldi AP (2013) Inositol pyrophosphates regulate cell growth and the environmental stress response by activating the HDAC Rpd3L. Cell Rep 3:1476–1482. https://doi.org/10.1016/j.celrep.2013.03.043
Wu M, Chong LS, Perlman DH, Resnick AC, Fiedler D (2016) Inositol polyphosphates intersect with signaling and metabolic networks via two distinct mechanisms. Proc Natl Acad Sci USA 113:E6757–E6765. https://doi.org/10.1073/pnas.1606853113
Wundenberg T, Grabinski N, Lin H, Mayr GW (2014) Discovery of InsP6-kinases as InsP6-dephosphorylating enzymes provides a new mechanism of cytosolic InsP6 degradation driven by the cellular ATP/ADP ratio. Biochem J 462:173–184. https://doi.org/10.1042/BJ20130992
York JD, Odom AR, Murphy R, Ives EB, Wente SR (1999) A phospholipase C-dependent inositol polyphosphate kinase pathway required for efficient messenger RNA export. Science 285:96–100
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by M. Kupiec.
Rights and permissions
About this article
Cite this article
Mutlu, N., Kumar, A. Messengers for morphogenesis: inositol polyphosphate signaling and yeast pseudohyphal growth. Curr Genet 65, 119–125 (2019). https://doi.org/10.1007/s00294-018-0874-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00294-018-0874-0