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Multiple interfaces control activity of the Candida glabrata Pdr1 transcription factor mediating azole drug resistance

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Abstract

The Cys6Zn2 DNA-binding domain transcription factor Pdr1 is a central regulator of drug resistance in the pathogenic yeast Candida glabrata. In this review, I discuss the multiple control mechanisms modulating the function of this positive transcriptional regulator. Available data suggest that Pdr1 activity is restrained by multiple negative inputs that can be lost by either mutagenesis of the protein or loss of trans-acting factors. Although extensive data are available on the C. glabrata transactivator as well as its cognate proteins in Saccharomyces cerevisiae, the physiological rationale underlying the regulation of these factors remains to be understood.

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References

  • Balzi E, Chen W, Ulaszewski S, Capieaux E, Goffeau A (1987) The multidrug resistance gene PDR1 from Saccharomyces cerevisiae. J Biol Chem 262:16871–16879

    CAS  PubMed  Google Scholar 

  • Balzi E, Wang M, Leterme S, Van Dyck L, Goffeau A (1994) PDR5: a novel yeast multidrug resistance transporter controlled by the transcription regulator PDR1. J Biol Chem 269:2206–2214

    CAS  PubMed  Google Scholar 

  • Bissinger PH, Kuchler K (1994) Molecular cloning and expression of the S. cerevisiae STS1 gene product. J Biol Chem 269:4180–4186

    CAS  PubMed  Google Scholar 

  • Bojsen R, Regenberg B, Folkesson A (2017) Persistence and drug tolerance in pathogenic yeast. Curr Genet 63(1):19–22

    Article  CAS  PubMed  Google Scholar 

  • Carvajal E, van den Hazel HB, Cybularz-Kolaczkowska A, Balzi E, Goffeau A (1997) Molecular and phenotypic characterization of yeast PDR1 mutants that show hyperactive transcription of various ABC multidrug transporter genes. Mol Gen Genet 256:406–415

    Article  CAS  PubMed  Google Scholar 

  • Caudle KE, Barker KS, Wiederhold NP, Xu L, Homayouni R, Rogers PD (2011) Genomewide expression profile analysis of the Candida glabrata Pdr1 regulon. Eukaryot Cell 10(3):373–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Contamine V, Picard M (2000) Maintenance and integrity of the mitochondrial genome: a plethora of nuclear genes in the budding yeast. Microbiol Mol Biol Rev 64:281–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Craig E, Ziegelhoffer T, Nelson J, Laloraya S, Halladay J (1995) Complex multigene family of functionally distinct Hsp70s of yeast. Cold Spring Harb Symp Quant Biol 60:441–449

    Article  CAS  PubMed  Google Scholar 

  • Delahodde A, Delaveau T, Jacq C (1995) Positive autoregulation of the yeast transcription factor Pdr3p, involved in the control of the drug resistance phenomenon. Mol Cell Biol 15:4043–4051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delaveau T, Delahodde A, Carvajal E, Subik J, Jacq C (1994) PDR3, a new yeast regulatory gene, is homologous to PDR1 and controls the multidrug resistance phenomenon. Mol Gen Genet 244:501–511

    Article  CAS  PubMed  Google Scholar 

  • Ducett JK, Peterson FC, Hoover LA, Prunuske AJ, Volkman BF, Craig EA (2013) Unfolding of the C-terminal domain of the J-protein Zuo1 releases autoinhibition and activates Pdr1-dependent transcription. J Mol Biol 425(1):19–31

    Article  CAS  PubMed  Google Scholar 

  • Eisenman HC, Craig EA (2004) Activation of pleiotropic drug resistance by the J-protein and Hsp70-related proteins, Zuo1 and Ssz1. Mol Microbiol 53(1):335–344

    Article  CAS  PubMed  Google Scholar 

  • Ferrari S, Ischer F, Calabrese D, Posteraro B, Sanguinetti M, Fadda G, Rohde B, Bauser C, Bader O, Sanglard D (2009) Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog 5(1):e1000268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gabaldon T, Fairhead C (2018) Genomes shed light on the secret life of Candida glabrata: not so asexual, not so commensal. Curr Genet. https://doi.org/10.1007/s00294-018-0867-z

    Article  PubMed  PubMed Central  Google Scholar 

  • Gulshan K, Schmidt J, Shahi P, Moye-Rowley WS (2008) Evidence for the bifunctional nature of mitochondrial phosphatidylserine decarboxylase: role in Pdr3-dependent retrograde regulation of PDR5 expression. Mol Cell Biol 28:5851–5864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hallstrom TC, Moye-Rowley WS (2000a) Hyperactive forms of the Pdr1p transcription factor fail to respond to positive regulation by the Hsp70 protein Pdr13p. Mol Microbiol 36:402–413

    Article  CAS  PubMed  Google Scholar 

  • Hallstrom TC, Moye-Rowley WS (2000b) Multiple signals from dysfunctional mitochondria activate the pleiotropic drug resistance pathway in Saccharomyces cerevisiae. J Biol Chem 275:37347–37356

    Article  CAS  PubMed  Google Scholar 

  • Hallstrom TC, Katzmann DJ, Torres RJ, Sharp WJ, Moye-Rowley WS (1998) Regulation of transcription factor Pdr1p function by a Hsp70 protein in Saccharomyces cerevisiae. Mol Cell Biol 18:1147–1155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirata D, Yano K, Miyahara K, Miyakawa T (1994) Saccharomyces cerevisiae YDR1, which encodes a member of the ATP-binding cassette (ABC) superfamily, is required for multidrug resistance. Curr Genet 26:285–294

    Article  CAS  PubMed  Google Scholar 

  • Hwang WW, Venkatasubrahmanyam S, Ianculescu AG, Tong A, Boone C, Madhani HD (2003) A conserved RING finger protein required for histone H2B monoubiquitination and cell size control. Mol Cell 11(1):261–266

    Article  CAS  PubMed  Google Scholar 

  • Kean LS, Grant AM, Angeletti C, Mahé Y, Kuchler K, Fuller RS, Nichols JW (1997) Plasma membrane translocation of fluorescent-labeled phosphatidylethanolamine is controlled by transcription regulators, PDR1 and PDR3. J Cell Biol 138:255–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khakhina S, Simonicova L, Moye-Rowley WS (2018) Positive autoregulation and repression of transactivation are key regulatory features of the Candida glabrata Pdr1 transcription factor. Mol Microbiol 107(6):747–764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mogk A, Bukau B, Kampinga HH (2018) Cellular handling of protein aggregates by disaggregation machines. Mol Cell 69(2):214–226

    Article  CAS  PubMed  Google Scholar 

  • Morschhauser J (2010) Regulation of multidrug resistance in pathogenic fungi. Fungal Genet Biol 47(2):94–106

    Article  CAS  PubMed  Google Scholar 

  • Moye-Rowley WS (2005) Retrograde regulation of multidrug resistance in Saccharomyces cerevisiae. Gene 354:15–21

    Article  CAS  PubMed  Google Scholar 

  • Nishikawa JL, Boeszoermenyi A, Vale-Silva LA, Torelli R, Posteraro B, Sohn YJ, Ji F, Gelev V, Sanglard D, Sanguinetti M, Sadreyev RI, Mukherjee G, Bhyravabhotla J, Buhrlage SJ, Gray NS, Wagner G, Naar AM, Arthanari H (2016) Inhibiting fungal multidrug resistance by disrupting an activator–mediator interaction. Nature 530(7591):485–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nourani A, Papajova D, Delahodde A, Jacq C, Subik J (1997) Clustered amino acid substitutions in the yeast transcription regulator Pdr3p increase pleiotropic drug resistance and identify a new central regulatory domain. Mol Gen Genet 256:397–405

    Article  CAS  PubMed  Google Scholar 

  • Paul S, Moye-Rowley WS (2014) Multidrug resistance in fungi: regulation of transporter-encoding gene expression. Front Physiol 5:143

    Article  PubMed  PubMed Central  Google Scholar 

  • Paul S, Schmidt JA, Moye-Rowley WS (2011) Regulation of the CgPdr1 transcription factor from the pathogen Candida glabrata. Eukaryot Cell 10(2):187–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paul S, Bair TB, Moye-Rowley WS (2014) Identification of genomic binding sites for Candida glabrata Pdr1 transcription factor in wild-type and rho0 cells. Antimicrob Agents Chemother 58(11):6904–6912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pfaller MA, Andes DR, Diekema DJ, Horn DL, Reboli AC, Rotstein C, Franks B, Azie NE (2014) Epidemiology and outcomes of invasive candidiasis due to non-albicans species of Candida in 2496 patients: data from the prospective antifungal therapy (path) registry 2004–2008. PLoS One 9(7):e101510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piskacek M, Havelka M, Rezacova M, Knight A (2016) The 9aaTAD transactivation domains: from Gal4 to p53. PLoS One 11(9):e0162842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rank GH, Bech-Hansen NT (1973) Single nuclear gene inherited cross resistance and collateral sensitivity to 17 inhibitors of mitochondrial function in Saccharomyces cerevisiae. Mol Gen Genet 126:93–102

    Article  CAS  PubMed  Google Scholar 

  • Sanglard D, Ischer F, Bille J (2001) Role of ATP-binding cassette transporter gene in high-frequency acquisition of resistance to azole antifungals in Candida glabrata. Antimicrob Agents Chemother 45:1174–1183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanglard D, Coste A, Ferrari S (2009) Antifungal drug resistance mechanisms in fungal pathogens from the perspective of transcriptional gene regulation. FEMS Yeast Res 9(7):1029–1050

    Article  CAS  PubMed  Google Scholar 

  • Schjerling P, Holmberg S (1996) Comparative amino acid sequence analysis of the C6 zinc cluster family of transcriptional regulators. Nucleic Acids Res 24:4599–4607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shahi P, Gulshan K, Moye-Rowley WS (2007) Negative transcriptional regulation of multidrug resistance gene expression by an Hsp70 protein. J Biol Chem 282(37):26822–26831

    Article  CAS  PubMed  Google Scholar 

  • Simonics T, Kozovska Z, Michalkova-Papajova D, Delahodde A, Jacq C, Subik J (2000) Isolation and molecular characterization of the carboxy-terminal pdr3 mutants in Saccharomyces cerevisiae. Curr Genet 38:248–255

    Article  CAS  PubMed  Google Scholar 

  • Soutourina J (2018) Transcription regulation by the mediator complex. Nat Rev Mol Cell Biol 19(4):262–274

    Article  CAS  PubMed  Google Scholar 

  • Thakur JK, Arthanari H, Yang F, Pan S-J, Fan X, Breger J, Frueh DP, Gulshan K, Li D, Mylonakis E, Struhl K, Moye-Rowley WS, Cormack BP, Wagner G, Naar AM (2008) A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature 452:604–609

    Article  CAS  PubMed  Google Scholar 

  • Traven A, Wong JM, Xu D, Sopta M, Ingles CJ (2001) Interorganellar communication. Altered nuclear gene expression profiles in a yeast mitochondrial DNA mutant. J Biol Chem 276:4020–4027

    Article  CAS  PubMed  Google Scholar 

  • Tsai HF, Krol AA, Sarti KE, Bennett JE (2006) Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants. Antimicrob Agents Chemother 50(4):1384–1392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsai HF, Sammons LR, Zhang X, Suffis SD, Su Q, Myers TG, Marr KA, Bennett JE (2010) Microarray and molecular analyses of the azole resistance mechanism in Candida glabrata oropharyngeal isolates. Antimicrob Agents Chemother 54(8):3308–3317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vermitsky JP, Edlind TD (2004) Azole resistance in Candida glabrata: coordinate upregulation of multidrug transporters and evidence for a Pdr1-like transcription factor. Antimicrob Agents Chemother 48(10):3773–3781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vermitsky JP, Earhart KD, Smith WL, Homayouni R, Edlind TD, Rogers PD (2006) Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies. Mol Microbiol 61(3):704–722

    Article  CAS  PubMed  Google Scholar 

  • Whaley SG, Caudle KE, Simonicova L, Zhang Q, Moye-Rowley WS, Rogers PD (2018) Jjj1 is a negative regulator of Pdr1-mediated fluconazole resistance in Candida glabrata. mSphere 3(1):e00466-17

    Article  PubMed  PubMed Central  Google Scholar 

  • Wiederhold NP (2017) Antifungal resistance: current trends and future strategies to combat. Infect Drug Resist 10:249–259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Kolaczkowska A, Devaux F, Panwar SL, Hallstrom TC, Jacq C, Moye-Rowley WS (2005) Transcriptional regulation by Lge1p requires a function independent of its role in histone H2B ubiquitination. J Biol Chem 280(4):2759–2770

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by NIH GM49825. I thank Dr. Lucia Simonicova for a critical reading of this review.

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  1. Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA

    W. Scott Moye-Rowley

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  1. W. Scott Moye-Rowley
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Correspondence to W. Scott Moye-Rowley.

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Communicated by M. Kupiec.

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Moye-Rowley, W.S. Multiple interfaces control activity of the Candida glabrata Pdr1 transcription factor mediating azole drug resistance. Curr Genet 65, 103–108 (2019). https://doi.org/10.1007/s00294-018-0870-4

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