All Title Author
Keywords Abstract


The bZIP Transcription Factor Rca1p Is a Central Regulator of a Novel CO2 Sensing Pathway in Yeast

DOI: 10.1371/journal.ppat.1002485

Full-Text   Cite this paper   Add to My Lib

Abstract:

Like many organisms the fungal pathogen Candida albicans senses changes in the environmental CO2 concentration. This response involves two major proteins: adenylyl cyclase and carbonic anhydrase (CA). Here, we demonstrate that CA expression is tightly controlled by the availability of CO2 and identify the bZIP transcription factor Rca1p as the first CO2 regulator of CA expression in yeast. We show that Rca1p upregulates CA expression during contact with mammalian phagocytes and demonstrate that serine 124 is critical for Rca1p signaling, which occurs independently of adenylyl cyclase. ChIP-chip analysis and the identification of Rca1p orthologs in the model yeast Saccharomyces cerevisiae (Cst6p) point to the broad significance of this novel pathway in fungi. By using advanced microscopy we visualize for the first time the impact of CO2 build-up on gene expression in entire fungal populations with an exceptional level of detail. Our results present the bZIP protein Rca1p as the first fungal regulator of carbonic anhydrase, and reveal the existence of an adenylyl cyclase independent CO2 sensing pathway in yeast. Rca1p appears to regulate cellular metabolism in response to CO2 availability in environments as diverse as the phagosome, yeast communities or liquid culture.

References

[1]  Gaugler CD, Lebeck L, Nakagaki B, Boush GM (1980) Orientation of the entomogenous nematode Neoaplectana carpocapsae to carbon dioxide. Environ Entomol 9: 649–652.
[2]  Bretscher AJ, Busch KE, de Bono M (2008) A carbon dioxide avoidance behavior is integrated with responses to ambient oxygen and food in Caenorhabditis elegans. Proc Natl Acad Sci U S A 105: 8044–8049.
[3]  Suh GS, Wong AM, Hergarden AC, Wang JW, Simon AF, et al. (2004) A single population of olfactory sensory neurons mediates an innate avoidance behaviour in Drosophila. Nature 431: 854–859.
[4]  Jones WD, Cayirlioglu P, Kadow IG, Vosshall LB (2007) Two chemosensory receptors together mediate carbon dioxide detection in Drosophila. Nature 445: 86–90.
[5]  Lindskog S (1997) Structure and mechanism of carbonic anhydrase. Pharmacol Ther 74: 1–20.
[6]  Gotz R, Gnann A, Zimmermann FK (1999) Deletion of the carbonic anhydrase-like gene NCE103 of the yeast Saccharomyces cerevisiae causes an oxygen-sensitive growth defect. Yeast 15: 855–864.
[7]  Klengel T, Liang WJ, Chaloupka J, Ruoff C, Schroppel K, et al. (2005) Fungal adenylyl cyclase integrates CO2 sensing with cAMP signaling and virulence. Curr Biol 15: 2021–2026.
[8]  Elleuche S, Poggeler S (2009) Beta-carbonic anhydrases play a role in fruiting body development and ascospore germination in the filamentous fungus Sordaria macrospora. PLoS One 4: e5177.
[9]  Han KH, Chun YH, Figueiredo Bde C, Soriani FM, Savoldi M, et al. (2010) The conserved and divergent roles of carbonic anhydrases in the filamentous fungi Aspergillus fumigatus and Aspergillus nidulans. Mol Microbiol 75: 1372–1388.
[10]  Bahn YS, Cox GM, Perfect JR, Heitman J (2005) Carbonic anhydrase and CO2 sensing during Cryptococcus neoformans growth, differentiation, and virulence. Curr Biol 15: 2013–2020.
[11]  Huang G, Srikantha T, Sahni N, Yi S, Soll DR (2009) CO(2) regulates white-to-opaque switching in Candida albicans. Curr Biol 19: 330–334.
[12]  Mogensen EG, Janbon G, Chaloupka J, Steegborn C, Fu MS, et al. (2006) Cryptococcus neoformans senses CO2 through the carbonic anhydrase Can2 and the adenylyl cyclase Cac1. Eukaryot Cell 5: 103–111.
[13]  Hall RA, De Sordi L, Maccallum DM, Topal H, Eaton R, et al. (2010) CO(2) acts as a signalling molecule in populations of the fungal pathogen Candida albicans. PLoS Pathog 6: e1001193.
[14]  Neri D, Supuran CT (2011) Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov 10: 767–77.
[15]  Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, et al. (2000) Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60: 7075–7083.
[16]  Kovacikova G, Lin W, Skorupski K (2010) The LysR-type virulence activator AphB regulates the expression of genes in Vibrio cholerae in response to low pH and anaerobiosis. J Bacteriol 192: 4181–4191.
[17]  Aguilera J, Petit T, de Winde JH, Pronk JT (2005) Physiological and genome-wide transcriptional responses of Saccharomyces cerevisiae to high carbon dioxide concentrations. FEMS Yeast Res 5: 579–593.
[18]  Amoroso G, Morell-Avrahov L, Muller D, Klug K, Sultemeyer D (2005) The gene NCE103 (YNL036w) from Saccharomyces cerevisiae encodes a functional carbonic anhydrase and its transcription is regulated by the concentration of inorganic carbon in the medium. Mol Microbiol 56: 549–558.
[19]  Rocha CR, Schroppel K, Harcus D, Marcil A, Dignard D, et al. (2001) Signaling through adenylyl cyclase is essential for hyphal growth and virulence in the pathogenic fungus Candida albicans. Mol Biol Cell 12: 3631–3643.
[20]  Fonzi WA, Irwin MY (1993) Isogenic strain construction and gene mapping in Candida albicans. Genetics 134: 717–728.
[21]  Lorenz MC, Bender JA, Fink GR (2004) Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot Cell 3: 1076–1087.
[22]  Lorenz MC, Fink GR (2001) The glyoxylate cycle is required for fungal virulence. Nature 412: 83–86.
[23]  Garcia-Gimeno MA, Struhl K (2000) Aca1 and Aca2, ATF/CREB activators in Saccharomyces cerevisiae, are important for carbon source utilization but not the response to stress. Mol Cell Biol 20: 4340–4349.
[24]  Srikantha T, Borneman AR, Daniels KJ, Pujol C, Wu W, et al. (2006) TOS9 regulates white-opaque switching in Candida albicans. Eukaryot Cell 5: 1674–1687.
[25]  Znaidi S, Barker KS, Weber S, Alarco AM, Liu TT, et al. (2009) Identification of the Candida albicans Cap1p regulon. Eukaryot Cell 8: 806–820.
[26]  Bates S, Hughes HB, Munro CA, Thomas WP, MacCallum DM, et al. (2006) Outer chain N-glycans are required for cell wall integrity and virulence of Candida albicans. J Biol Chem 281: 90–98.
[27]  Elson SL, Noble SM, Solis NV, Filler SG, Johnson AD (2009) An RNA transport system in Candida albicans regulates hyphal morphology and invasive growth. PLoS Genet 5: e1000664.
[28]  Vachova L, Chernyavskiy O, Strachotova D, Bianchini P, Burdikova Z, et al. (2009) Architecture of developing multicellular yeast colony: spatio-temporal expression of Ato1p ammonium exporter. Environ Microbiol 11: 1866–77.
[29]  Schmid A, Sutto Z, Schmid N, Novak L, Ivonnet P, et al. (2010) Decreased soluble adenylyl cyclase activity in cystic fibrosis is related to defective apical bicarbonate exchange and affects ciliary beat frequency regulation. J Biol Chem 285: 29998–30007.
[30]  Supuran CT (2008) Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7: 168–181.
[31]  Schlicker C, Hall RA, Vullo D, Middelhaufe S, Gertz M, et al. (2009) Structure and inhibition of the CO2-sensing carbonic anhydrase Can2 from the pathogenic fungus Cryptococcus neoformans. J Mol Biol 385: 1207–1220.
[32]  Schofield CJ, Ratcliffe PJ (2005) Signalling hypoxia by HIF hydroxylases. Biochem Biophys Res Commun 338: 617–626.
[33]  Parks SK, Chiche J, Pouyssegur J (2011) pH control mechanisms of tumor survival and growth. J Cell Physiol 226: 299–308.
[34]  Setiadi ER, Doedt T, Cottier F, Noffz C, Ernst JF (2006) Transcriptional response of Candida albicans to hypoxia: linkage of oxygen sensing and Efg1p-regulatory networks. J Mol Biol 361: 399–411.
[35]  Carlson JM, Chakravarty A, DeZiel CE, Gross RH (2007) SCOPE: a web server for practical de novo motif discovery. Nucleic Acids Res 35: W259–264.
[36]  Taylor JW, Berbee ML (2006) Dating divergences in the Fungal Tree of Life: review and new analyses. Mycologia 98: 838–849.
[37]  Lavoie H, Hogues H, Mallick J, Sellam A, Nantel A (2010) Evolutionary tinkering with conserved components of a transcriptional regulatory network. PLoS Biol 8: e1000329.
[38]  Kaluz S, Kaluzova M, Liao SY, Lerman M, Stanbridge EJ (2009) Transcriptional control of the tumor- and hypoxia-marker carbonic anhydrase 9: A one transcription factor (HIF-1) show? Biochim Biophys Acta 1795: 162–172.
[39]  Brennan DJ, Jirstrom K, Kronblad A, Millikan RC, Landberg G, et al. (2006) CA IX is an independent prognostic marker in premenopausal breast cancer patients with one to three positive lymph nodes and a putative marker of radiation resistance. Clin Cancer Res 12: 6421–6431.
[40]  Demirci A, Pometto AL 3rd, Ho KL (1997) Ethanol production by Saccharomyces cerevisiae in biofilm reactors. J Ind Microbiol Biotechnol 19: 299–304.
[41]  Zara S, Gross MK, Zara G, Budroni M, Bakalinsky AT (2010) Ethanol-independent biofilm formation by a flor wine yeast strain of Saccharomyces cerevisiae. Appl Environ Microbiol 76: 4089–4091.
[42]  Huang G, Yi S, Sahni N, Daniels KJ, Srikantha T, et al. (2010) N-acetylglucosamine induces white to opaque switching, a mating prerequisite in Candida albicans. PLoS Pathog 6: e1000806.
[43]  Liu TT, Znaidi S, Barker KS, Xu L, Homayouni R, et al. (2007) Genome-wide expression and location analyses of the Candida albicans Tac1p regulon. Eukaryot Cell 6: 2122–2138.
[44]  Zhang ZD, Rozowsky J, Lam HY, Du J, Snyder M, et al. (2007) Tilescope: online analysis pipeline for high-density tiling microarray data. Genome Biol 8: R81.

Full-Text

comments powered by Disqus