Two glutathione peroxidases in the fungal pathogen Cryptococcus neoformans are expressed in the presence of specific substrates

Missall, Tricia A.; Cherry-Harris, Jocie F.; Lodge, Jennifer K.

doi:10.1099/mic.0.28132-0

Cited by 56 publications

(37 citation statements)

References 29 publications

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“…Missall et al demonstrated that TSA1, one of three C. neoformans thiol peroxidase genes, and the glutathione peroxidase genes GPX1 and GPX2 contribute to protection against oxidative stress in vitro (36,37). In addition, TSA1 has contributed to virulence in a murine model of cryptococcosis (36,37). The results of these studies suggest that the C. neoformans antioxidant system is composed of several functionally overlapping and compensatory components that provide protection against endogenous and exogenous oxidative stresses.…”

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confidence: 60%

“…This resistance can be accomplished in a number of different ways, including the production of factors that prevent host effector cells from eliciting an oxidative burst, the possession of nonenzymatic antioxidants (such as melanin and mannitol), and the utilization of enzymatic antioxidants (such as catalases, superoxide dismutases, and various peroxidases) to degrade ROS. The complexity of the antioxidant defense system is illustrated by the retained ability of many C. neoformans mutants with antioxidant defense defects to cause morbidity and mortality in a manner undistinguishable from that of wild-type strains (20,36). C. neoformans can colonize the lung, which suggests that it possesses adequate antioxidant defenses to overcome the oxygen-dependent killing mechanisms of alveolar macrophages (14,15,29,30,42,50,52) and other host phagocytes.…”

Section: Discussionmentioning

confidence: 99%

“…gattii (40,41), which can cause disease in immunocompetent individuals (17). Missall et al demonstrated that TSA1, one of three C. neoformans thiol peroxidase genes, and the glutathione peroxidase genes GPX1 and GPX2 contribute to protection against oxidative stress in vitro (36,37). In addition, TSA1 has contributed to virulence in a murine model of cryptococcosis (36,37).…”

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TheCryptococcus neoformansCatalase Gene Family and ItsRole in Antioxidant Defense

Giles¹,

Stajich

Nichols³

et al. 2006

Eukaryot Cell

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In the present study, we sought to elucidate the contribution of the Cryptococcus neoformans catalase gene family to antioxidant defense. We employed bioinformatics techniques to identify four members of the C. neoformans catalase gene family and created mutants lacking single or multiple catalase genes. Based on a phylogenetic analysis, CAT1 and CAT3 encode putative spore-specific catalases, CAT2 encodes a putative peroxisomal catalase, and CAT4 encodes a putative cytosolic catalase. Only Cat1 exhibited detectable biochemical activity in vitro, and Cat1 activity was constitutive in the yeast form of this organism. Although they were predicted to be important in spores, neither CAT1 nor CAT3 was essential for mating or spore viability. Consistent with previous studies of Saccharomyces cerevisiae, the single (cat1, cat2, cat3, and cat4) and quadruple (cat1 cat2 cat3 cat4) catalase mutant strains exhibited no oxidative-stress phenotypes under conditions in which either exogenous or endogenous levels of reactive oxygen species were elevated. In addition, there were no significant differences in the mean times to mortality between groups of mice infected with C. neoformans catalase mutant strains (the cat1 and cat1 cat2 cat3 cat4 mutants) and those infected with wild-type strain H99. We conclude from the results of this study that C. neoformans possesses a robust antioxidant system, composed of functionally overlapping and compensatory components that provide protection against endogenous and exogenous oxidative stresses.

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confidence: 60%

Section: Discussionmentioning

confidence: 99%

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TheCryptococcus neoformansCatalase Gene Family and ItsRole in Antioxidant Defense

Giles¹,

Stajich

Nichols³

et al. 2006

Eukaryot Cell

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“…Glutathione reductase is necessary for reducing the glutathione disulfide, which is formed as a by-product of glutathione peroxidases or glutaredoxins in the presence of reactive oxygen or nitrogen species. The importance of the glutathione peroxidases in C. neoformans to the oxidative stress response has recently been described (32), but enzymes of the glutathione system have yet to be shown to be important for the nitrosative stress response in any organism. We find that mutants deficient in Glr1 are sensitive to nitric oxide stress, but not peroxide stress, revealing a specificity between oxidative and nitrosative stress resistance mechanisms in C. neoformans.…”

Section: Discussionmentioning

confidence: 99%

Posttranslational, Translational, and Transcriptional Responses to Nitric Oxide Stress in Cryptococcus neoformans : Implications for Virulence

Missall¹,

Pusateri²,

Donlin

et al. 2006

Eukaryot Cell

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The ability of the fungal pathogen Cryptococcus neoformans to evade the mammalian innate immune response and cause disease is partially due to its ability to respond to and survive nitrosative stress. In this study, we use proteomic and genomic approaches to elucidate the response of C. neoformans to nitric oxide stress. This nitrosative stress response involves both transcriptional, translational, and posttranslational regulation. Proteomic and genomic analyses reveal changes in expression of stress response genes. In addition, genes involved in cell wall organization, respiration, signal transduction, transport, transcriptional control, and metabolism show altered expression under nitrosative conditions. Posttranslational modifications of transaldolase (Tal1), aconitase (Aco1), and the thiol peroxidase, Tsa1, are regulated during nitrosative stress. One stress-related protein up-regulated in the presence of nitric oxide stress is glutathione reductase (Glr1). To further investigate its functional role during nitrosative stress, a deletion mutant was generated. We show that this glr1⌬ mutant is sensitive to nitrosative stress and macrophage killing in addition to being avirulent in mice. These studies define the response to nitrosative stress in this important fungal pathogen.To survive the oxidative and nitrosative attack initiated by phagocytic cells of the host, pathogens must respond appropriately (reviewed in reference 35). This antimicrobial attack is established by two main systems including the inducible nitric oxide synthase pathway and the NADPH oxidase pathway (14). These two pathways generate either reactive nitrogen species (RNS) or reactive oxygen species. In the absence of either of these two pathways, mammalian hosts are more susceptible to both bacterial and fungal infections (18, 41). To cause infection, pathogens must evade the immune system by initiating a response to the stresses encountered.Previously, transcriptional responses to temperature, osmotic, and hydrogen peroxide stress as well as the stresses encountered in macrophages have been studied in fungi, including Saccharomyces cerevisiae and Candida albicans (13,25,29). A proteomic response to stress has only been determined in S. cerevisiae during hydrogen peroxide exposure (17). Proteomic analysis of the nitrosative stress response has not been studied in fungi, though transcriptional responses to RNS have been recently described in S. cerevisiae, C. albicans, and Histoplasma capsulatum (21,39,46). Though the response to nitrosative stress has not been studied in Cryptococcus neoformans, it has been implicated in both stress resistance and virulence of this fungal pathogen (10,33,36). It has been shown that macrophages produce nitric oxide in response to cryptococcal cells (20) and that the anticryptococcal activity of macrophages is mostly dependent on RNS (48). Recently, it was determined that during experimental cryptococcosis, the inducible form of nitric oxide synthase (iNOS) is expressed at increasing levels during infection (...

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“…The intracellular pathogenicity of C. neoformans is most likely facilitated by stress resistance mechanisms, including a number of antioxidant proteins and pathways involved in the detoxification of ROS and RNS. Specifically, these include the synthesis of mannitol, a free radical scavenger (9,20); the small protein flavohemoglobin denitrosylase (Fhb1), which is essential for resistance of C. neoformans to nitrosative stress (10,14,32); and the glutathione and thioredoxin antioxidant systems, which are both important for stress resistance and virulence (42,43,45).…”

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Isocitrate Dehydrogenase Is Important for Nitrosative Stress Resistance in Cryptococcus neoformans, but Oxidative Stress Resistance Is Not Dependent on Glucose-6-Phosphate Dehydrogenase

et al. 2010

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The opportunistic intracellular fungal pathogen Cryptococcus neoformans depends on many antioxidant and denitrosylating proteins and pathways for virulence in the immunocompromised host. These include the glutathione and thioredoxin pathways, thiol peroxidase, cytochrome c peroxidase, and flavohemoglobin denitrosylase. All of these ultimately depend on NADPH for either catalytic activity or maintenance of a reduced, functional form. The need for NADPH during oxidative stress is well established in many systems, but a role in resistance to nitrosative stress has not been as well characterized. In this study we investigated the roles of two sources of NADPH, glucose-6-phosphate dehydrogenase (Zwf1) and NADP ؉ -dependent isocitrate dehydrogenase (Idp1), in production of NADPH and resistance to oxidative and nitrosative stress. Deletion of ZWF1 in C. neoformans did not result in an oxidative stress sensitivity phenotype or changes in the amount of NADPH produced during oxidative stress compared to those for the wild type. Deletion of IDP1 resulted in greater sensitivity to nitrosative stress than to oxidative stress. The amount of NADPH increased 2-fold over that in the wild type during nitrosative stress, and yet the idp1⌬ strain accumulated more mitochondrial damage than the wild type during nitrosative stress. This is the first report of the importance of Idp1 and NADPH for nitrosative stress resistance.

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Two glutathione peroxidases in the fungal pathogen Cryptococcus neoformans are expressed in the presence of specific substrates

Cited by 56 publications

References 29 publications

TheCryptococcus neoformansCatalase Gene Family and ItsRole in Antioxidant Defense

TheCryptococcus neoformansCatalase Gene Family and ItsRole in Antioxidant Defense

Posttranslational, Translational, and Transcriptional Responses to Nitric Oxide Stress in Cryptococcus neoformans : Implications for Virulence

Isocitrate Dehydrogenase Is Important for Nitrosative Stress Resistance in Cryptococcus neoformans, but Oxidative Stress Resistance Is Not Dependent on Glucose-6-Phosphate Dehydrogenase

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