Cryptococcus neoformans Yap1 is required for normal fluconazole and oxidative stress resistance

Paul, Sanjoy; Doering, Tamara L.; Moye‐Rowley, W. Scott

doi:10.1016/j.fgb.2014.10.015

Cited by 35 publications

(36 citation statements)

References 63 publications

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“…Nevertheless, the contradictory functions of AaTrr1 and AaGlr1 in response to mancozeb highlight the complexity of cellular resistance to any given fungicide. Cellular resistance to both oxidative stress and fluconazole mediated by the bZip transcription regulator Yap1 has also been reported in animal fungal pathogens (46,47).…”

Section: Figmentioning

confidence: 94%

Thioredoxin and Glutaredoxin Systems Required for Oxidative Stress Resistance, Fungicide Sensitivity, and Virulence of Alternaria alternata

Wang

Gai

et al. 2018

Appl Environ Microbiol

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This study determined the function of thioredoxin and glutaredoxin systems in the phytopathogenic fungus via analyzing mutants obtained from the targeted deletion of genes encoding thioredoxin peroxidase (), thioredoxin reductase (), and glutathione reductase (). and, but not , are required for growth and conidiation. The reduced growth and conidiation seen in the or deletion mutant can be restored by glutathione. Deletion mutants showing growth inhibition by oxidants are defective for HO detoxification and induce smaller lesions on citrus leaves. and, but not , also contribute to NaCl resistance. is required for sorbitol resistance and is responsible for resistance to mancozeb and boscalid but not chlorothalonil fungicides, a novel phenotype that has not been reported in fungi. is required for resistance to boscalid and chlorothalonil fungicides but confers susceptibility to mancozeb. The deletion mutant displays wild-type sensitivity to the tested fungicides. The expression of and is regulated by the oxidative stress responsive regulators Yap1, Hog1, and Skn7. The expression of , but not, is also regulated indirectly by the NADPH oxidase. The results indicate that the capability to resist oxidative stress is required for virulence of The thioredoxin and glutaredoxin systems are important thiol antioxidant systems in cells, and knowledge of these two systems in the plant-pathogenic fungus is useful for finding new strategies to reduce the virulence of this pathogen. In this study, we demonstrated that thiol antioxidant system-related genes (, , and) are required for HO detoxification and virulence in Moreover, deletion of results in hypersensitivity to the fungicides chlorothalonil and boscalid, and deletion mutants are highly sensitive to mancozeb, which is the fungicide mostly used in citrus fields. Therefore, our findings demonstrate that the ability to detoxify reactive oxygen species (ROS) plays a critical role in pathogenesis on citrus and provide novel insights into the physiological functions of thiol-containing systems in fungicide sensitivity for.

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Section: Figmentioning

confidence: 94%

Thioredoxin and Glutaredoxin Systems Required for Oxidative Stress Resistance, Fungicide Sensitivity, and Virulence of Alternaria alternata

Wang

Gai

et al. 2018

Appl Environ Microbiol

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“…Although we have not found any reports on anecdotal clinical cases of VRC-resistant and ITCsusceptible A. flavus strain so far, we are concerned with whether the VRC-resistant A. flavus obtained in this study can emerge and prevail in clinical settings. We indicated the presence of a novel VRC resistance mechanism caused by a mutant of the Yap1 transcriptional factor, which has been studied as a major regulator of the oxidative stress response in S. cerevisiae, C. albicans, C. glabrata, Cryptococcus neoformans, and A. fumigatus (42)(43)(44)(45)(46)(47)(48)(49)(50)(51). We found that genes having the putative YRE, such as atrF, dsba, and gst, were upregulated in the Yap1 L558W strain.…”

Section: Discussionmentioning

confidence: 95%

“…Gene expression levels of efflux transporters and possible Yap1 regulating genes. Yap1 has been known as the major regulator of responses to reactive oxygen species (ROS) stress in S. cerevisiae and pathogenic fungi (42)(43)(44)(45)(46)(47)(48)(49)(50)(51). Based on previous studies of S. cerevisiae (52)(53)(54)(55)(56)(57), the Leu558 residue in the A. flavus Yap1 is considered a key residue of the nuclear export signal (NES) that controls nuclear localization of Yap1.…”

Section: Whole-genome Sequencing Analysis Of Vrc-resistant a Flavusmentioning

confidence: 99%

Contributions of yap1 Mutation and Subsequent atrF Upregulation to Voriconazole Resistance in Aspergillus flavus

Ukai

Kuroiwa

Kurihara

et al. 2018

Antimicrob Agents Chemother

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is the second most significant pathogenic cause of invasive aspergillosis; however, its emergence risks and mechanisms of voriconazole (VRC) resistance have not yet been elucidated in detail. Here, we demonstrate that repeated exposure of to subinhibitory concentrations of VRC causes the emergence of a VRC-resistant mutant with a novel resistance mechanism. The VRC-resistant mutant shows a MIC of 16 μg/ml for VRC and of 0.5 μg/ml for itraconazole (ITC). Whole-genome sequencing analysis showed that the mutant possesses a point mutation in , which encodes a bZIP transcription factor working as the master regulator of the oxidative stress response, but no mutations in the genes. This point mutation in caused alteration of Leu558 to Trp (Yap1) in the putative nuclear export sequence in the carboxy-terminal cysteine-rich domain of Yap1. This Yap1 substitution was confirmed as being responsible for the VRC-resistant phenotype, but not for that of ITC, by the revertant to Yap1 with homologous gene replacement. Furthermore, Yap1 caused marked upregulation of the ATP-binding cassette transporter, and the deletion of restored susceptibility to VRC in These findings provide new insights into VRC resistance mechanisms via a transcriptional factor mutation that is independent of the gene mutation in .

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“…Interestingly, AP-1-like factors have been found to be dispensable for the virulence of the human fungal pathogens Aspergillus fumigatus (85), Cr. neoformans (86), and C. albicans (82, 87), but are required for the virulence of a number of plant pathogens (88–90). …”

Section: Adapting To Individual Stressesmentioning

confidence: 99%

Stress Adaptation

et al. 2017

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Fungal species display an extraordinarily diverse range of lifestyles. Nevertheless, the survival of each species depends on its ability to sense and respond to changes in its natural environment. Environmental changes such as fluctuations in temperature, water balance or pH, or exposure to chemical insults such as reactive oxygen and nitrogen species exert stresses that perturb cellular homeostasis and cause molecular damage to the fungal cell. Consequently, fungi have evolved mechanisms to repair this damage, detoxify chemical insults, and restore cellular homeostasis. Most stresses are fundamental in nature, and consequently, there has been significant evolutionary conservation in the nature of the resultant responses across the fungal kingdom and beyond. For example, heat shock generally induces the synthesis of chaperones that promote protein refolding, antioxidants are generally synthesized in response to an oxidative stress, and osmolyte levels are generally increased following a hyperosmotic shock. In this article we summarize the current understanding of these and other stress responses as well as the signaling pathways that regulate them in the fungi. Model yeasts such as Saccharomyces cerevisiae are compared with filamentous fungi, as well as with pathogens of plants and humans. We also discuss current challenges associated with defining the dynamics of stress responses and with the elaboration of fungal stress adaptation under conditions that reflect natural environments in which fungal cells may be exposed to different types of stresses, either sequentially or simultaneously.

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Cryptococcus neoformans Yap1 is required for normal fluconazole and oxidative stress resistance

Cited by 35 publications

References 63 publications

Thioredoxin and Glutaredoxin Systems Required for Oxidative Stress Resistance, Fungicide Sensitivity, and Virulence of Alternaria alternata

Thioredoxin and Glutaredoxin Systems Required for Oxidative Stress Resistance, Fungicide Sensitivity, and Virulence of Alternaria alternata

Contributions of yap1 Mutation and Subsequent atrF Upregulation to Voriconazole Resistance in Aspergillus flavus

Stress Adaptation

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