RESUMO
C. glabrata, an opportunistic fungal pathogen, can adapt and resist to different stress conditions. It is highly resistant to oxidant stress compared to other Candida spp and to the phylogenetically related but non-pathogen Saccharomyces cerevisiae. In this work, we describe the Trx/Trr system of C. glabrata composed of Trr1 and Trr2 (thioredoxin reductases) and Trx2 (thioredoxin) that are localized in the cytoplasm and Trx3 present in the mitochondrion. The transcriptional induction of TRR2 and TRX2 by oxidants depends on Yap1 and Skn7 and TRR1 and TRX3 have a low expression level. Both TRR2 and TRX2 play an important role in the oxidative stress response. The absence of TRX2 causes auxotrophy of methionine and cysteine. Trr1 and Trr2 are necessary for survival at high temperatures and for the chronological life span of C. glabrata. Furthermore, the Trx/Trr system is needed for survival in the presence of neutrophils. The role of TRR1 and TRX3 is not clear, but in the presence of neutrophils, they have non-overlapping functions with their TRR2 and TRX2 paralogues.
Assuntos
Candida glabrata , Saccharomyces cerevisiae , Candida glabrata/genética , Saccharomyces cerevisiae/metabolismo , Oxidantes/metabolismo , Oxidantes/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Estresse Oxidativo/genética , Tiorredoxinas/genética , Tiorredoxinas/metabolismoRESUMO
Candida glabrata has emerged as an important opportunistic pathogen in both mucosal and bloodstream infections. C. glabrata contains 67 adhesin-like glycosylphosphatidylinositol-cell-wall proteins (GPI-CWPs), which are classified into seven groups and the largest is the Epa family. Epa proteins are very diverse and their expression is differentially regulated. Like many of the EPA genes, EPA2 is localized in a subtelomeric region where it is subject to chromatin-based transcriptional silencing and its role remains largely unexplored. In this study, we show that EPA2 gene is induced specifically in vitro in the presence of oxidative stress generated by H2O2. This induction is dependent on both Yap1 and Skn7, whereas Msn4 represses EPA2 expression. Interestingly, EPA2 is not induced during phagocytosis, but its expression can be identified in the liver in a murine model of systemic infection. Epa2 has no effect on the virulence of C. glabrata. The work presented herein provides a foundation for future studies to dissect the molecular mechanism(s) by which EPA2 of C. glabrata can be induced in the presence of oxidative stress in a region subject to subtelomeric silencing.
Assuntos
Candida glabrata/genética , Candida glabrata/patogenicidade , Moléculas de Adesão Celular/genética , Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica , Fatores de Transcrição/genética , Animais , Candida glabrata/efeitos dos fármacos , Candida glabrata/metabolismo , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Moléculas de Adesão Celular/metabolismo , Proteínas Fúngicas/metabolismo , Inativação Gênica , Peróxido de Hidrogênio/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , Estresse Oxidativo , Fagocitose/genética , Telômero/química , Telômero/metabolismo , Fatores de Transcrição/metabolismo , VirulênciaRESUMO
The fungal pathogen Candida glabrata has a well-defined oxidative stress response, is extremely resistant to oxidative stress and can survive inside phagocytic cells. In order to further our understanding of the oxidative stress response in C. glabrata, we characterized the superoxide dismutases (SODs) Cu,ZnSOD (Sod1) and MnSOD (Sod2). We found that Sod1 is the major contributor to total SOD activity and is present in cytoplasm, whereas Sod2 is a mitochondrial protein. Both SODs played a central role in the oxidative stress response but Sod1 was more important during fermentative growth and Sod2 during respiration and growth in non-fermentable carbon sources. Interestingly, C. glabrata cells lacking both SODs showed auxotrophy for lysine, a high rate of spontaneous mutation and reduced chronological lifespan. Thus, our study reveals that SODs play an important role in metabolism, lysine biosynthesis, DNA protection and aging in C. glabrata.