A New Regulator in the Crossroads of Oxidative Stress Resistance and Virulence in : The Transcription Factor CgTog1

Overview

Journal Virulence

Specialty Microbiology

Date 2020 Nov 2

PMID 33135521

Citations 6

Authors

Pedro Pais

Susana Vagueiro

Dalila Mil-Homens

Andreia I Pimenta

Romeu Viana

Michiyo Okamoto

Hiroji Chibana

Arsenio M Fialho

Miguel C Teixeira

Affiliations

Soon will be listed here.

Abstract

is a prominent pathogenic yeast which exhibits a unique ability to survive the harsh environment of host immune cells. In this study, we describe the role of the transcription factor encoded by the gene , here named CgTog1 after its ortholog, as a new determinant of virulence. Interestingly, Tog1 is absent in the other clinically relevant species (), being exclusive to . CgTog1 was found to be required for oxidative stress resistance and for the modulation of reactive oxygen species inside cells. Also, CgTog1 was observed to be a nuclear protein, whose activity up-regulates the expression of 147 genes and represses 112 genes in cells exposed to HO, as revealed through RNA-seq-based transcriptomics analysis. Given the importance of oxidative stress response in the resistance to host immune cells, the effect of expression in yeast survival upon phagocytosis by hemocytes was evaluated, leading to the identification of CgTog1 as a determinant of yeast survival upon phagocytosis. Interestingly, CgTog1 targets include many whose expression changes in cells after engulfment by macrophages, including those involved in reprogrammed carbon metabolism, glyoxylate cycle and fatty acid degradation. In summary, CgTog1 is a new and specific regulator of virulence in , contributing to oxidative stress resistance and survival upon phagocytosis by host immune cells.

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References

Pais P, Costa C, Pires C, Shimizu K, Chibana H, Teixeira M . Membrane Proteome-Wide Response to the Antifungal Drug Clotrimazole in Candida glabrata: Role of the Transcription Factor CgPdr1 and the Drug:H+ Antiporters CgTpo1_1 and CgTpo1_2. Mol Cell Proteomics. 2015; 15(1):57-72. PMC: 4762512. DOI: 10.1074/mcp.M114.045344. View

Thepnok P, Ratanakhanokchai K, Soontorngun N . The novel zinc cluster regulator Tog1 plays important roles in oleate utilization and oxidative stress response in Saccharomyces cerevisiae. Biochem Biophys Res Commun. 2014; 450(4):1276-82. DOI: 10.1016/j.bbrc.2014.06.128. View

Lorenz M, Bender J, Fink G . Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot Cell. 2004; 3(5):1076-87. PMC: 522606. DOI: 10.1128/EC.3.5.1076-1087.2004. View

Pais P, Galocha M, Teixeira M . Genome-Wide Response to Drugs and Stress in the Pathogenic Yeast Candida glabrata. Prog Mol Subcell Biol. 2019; 58:155-193. DOI: 10.1007/978-3-030-13035-0_7. View

Vermitsky J, Earhart K, Smith W, Homayouni R, Edlind T, Rogers P . Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies. Mol Microbiol. 2006; 61(3):704-22. DOI: 10.1111/j.1365-2958.2006.05235.x. View

Saijo T, Miyazaki T, Izumikawa K, Mihara T, Takazono T, Kosai K . Skn7p is involved in oxidative stress response and virulence of Candida glabrata. Mycopathologia. 2009; 169(2):81-90. DOI: 10.1007/s11046-009-9233-5. View

Grant C, MacIver F, Dawes I . Mitochondrial function is required for resistance to oxidative stress in the yeast Saccharomyces cerevisiae. FEBS Lett. 1997; 410(2-3):219-22. DOI: 10.1016/s0014-5793(97)00592-9. View

Monteiro P, Oliveira J, Pais P, Antunes M, Palma M, Cavalheiro M . YEASTRACT+: a portal for cross-species comparative genomics of transcription regulation in yeasts. Nucleic Acids Res. 2019; 48(D1):D642-D649. PMC: 6943032. DOI: 10.1093/nar/gkz859. View

Luttik M, Kotter P, Salomons F, van der Klei I, van Dijken J, Pronk J . The Saccharomyces cerevisiae ICL2 gene encodes a mitochondrial 2-methylisocitrate lyase involved in propionyl-coenzyme A metabolism. J Bacteriol. 2000; 182(24):7007-13. PMC: 94827. DOI: 10.1128/JB.182.24.7007-7013.2000. View

10.

Li L, Naseem S, Sharma S, Konopka J . Flavodoxin-Like Proteins Protect Candida albicans from Oxidative Stress and Promote Virulence. PLoS Pathog. 2015; 11(9):e1005147. PMC: 4556627. DOI: 10.1371/journal.ppat.1005147. View

11.

Costa C, Henriques A, Pires C, Nunes J, Ohno M, Chibana H . The dual role of candida glabrata drug:H+ antiporter CgAqr1 (ORF CAGL0J09944g) in antifungal drug and acetic acid resistance. Front Microbiol. 2013; 4:170. PMC: 3693063. DOI: 10.3389/fmicb.2013.00170. View

12.

Byrne K, Wolfe K . Visualizing syntenic relationships among the hemiascomycetes with the Yeast Gene Order Browser. Nucleic Acids Res. 2005; 34(Database issue):D452-5. PMC: 1347404. DOI: 10.1093/nar/gkj041. View

13.

Pais P, Galocha M, Viana R, Cavalheiro M, Pereira D, Teixeira M . Microevolution of the pathogenic yeasts and during antifungal therapy and host infection. Microb Cell. 2019; 6(3):142-159. PMC: 6402363. DOI: 10.15698/mic2019.03.670. View

14.

Seider K, Brunke S, Schild L, Jablonowski N, Wilson D, Majer O . The facultative intracellular pathogen Candida glabrata subverts macrophage cytokine production and phagolysosome maturation. J Immunol. 2011; 187(6):3072-86. DOI: 10.4049/jimmunol.1003730. View

15.

Haas A . The phagosome: compartment with a license to kill. Traffic. 2007; 8(4):311-30. DOI: 10.1111/j.1600-0854.2006.00531.x. View

16.

Galocha M, Pais P, Cavalheiro M, Pereira D, Viana R, Teixeira M . Divergent Approaches to Virulence in and : Two Sides of the Same Coin. Int J Mol Sci. 2019; 20(9). PMC: 6539081. DOI: 10.3390/ijms20092345. View

17.

Pais P, Pires C, Costa C, Okamoto M, Chibana H, Teixeira M . Membrane Proteomics Analysis of the Response to 5-Flucytosine: Unveiling the Role and Regulation of the Drug Efflux Transporters CgFlr1 and CgFlr2. Front Microbiol. 2017; 7:2045. PMC: 5174090. DOI: 10.3389/fmicb.2016.02045. View

18.

Jansen G, Wu C, Schade B, Thomas D, Whiteway M . Drag&Drop cloning in yeast. Gene. 2005; 344:43-51. DOI: 10.1016/j.gene.2004.10.016. View

19.

Monteiro P, Pais P, Costa C, Manna S, Sa-Correia I, Teixeira M . The PathoYeastract database: an information system for the analysis of gene and genomic transcription regulation in pathogenic yeasts. Nucleic Acids Res. 2016; 45(D1):D597-D603. PMC: 5210609. DOI: 10.1093/nar/gkw817. View

20.

Kuge S, Jones N, Nomoto A . Regulation of yAP-1 nuclear localization in response to oxidative stress. EMBO J. 1997; 16(7):1710-20. PMC: 1169774. DOI: 10.1093/emboj/16.7.1710. View