Glutathione Reductase/Glutathione Is Responsible for Cytotoxic Elemental Sulfur Tolerance via Polysulfide Shuttle in Fungi

Sato, Ikuo; Shimatani, Kanami; Fujita, Kensaku; Abe, Tsuyoshi; Shimizu, Motoyuki; Fujii, Tatsuya; Hoshino, Takayuki; Takaya, Naoki

doi:10.1074/jbc.m111.225979

Cited by 40 publications

(52 citation statements)

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“…This is possibly resulting in a decrease of the reduced glutathione pool, thus impairing the cellular redox balance. In fact, an interplay between the sulfur assimilatory pathway and the formation of the reduced form of glutathione, a powerful anti-oxidant [43], is well described in some fungi [44,45]. A similar observation was reported upon selenium uptake by S.…”

Section: Discussionmentioning

confidence: 66%

P. brasiliensis Virulence Is Affected by SconC, the Negative Regulator of Inorganic Sulfur Assimilation

et al. 2013

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Conidia/mycelium-to-yeast transition of Paracoccidioides brasiliensis is a critical step for the establishment of paracoccidioidomycosis, a systemic mycosis endemic in Latin America. Thus, knowledge of the factors that mediate this transition is of major importance for the design of intervention strategies. So far, the only known pre-requisites for the accomplishment of the morphological transition are the temperature shift to 37°C and the availability of organic sulfur compounds. In this study, we investigated the auxotrophic nature to organic sulfur of the yeast phase of Paracoccidioides , with special attention to P. brasiliensis species. For this, we addressed the role of SconCp, the negative regulator of the inorganic sulfur assimilation pathway, in the dimorphism and virulence of this pathogen. We show that down-regulation of SCONC allows initial steps of mycelium-to-yeast transition in the absence of organic sulfur compounds, contrarily to the wild-type fungus that cannot undergo mycelium-to-yeast transition under such conditions. However, SCONC down-regulated transformants were unable to sustain yeast growth using inorganic sulfur compounds only. Moreover, pulses with inorganic sulfur in SCONC down-regulated transformants triggered an increase of the inorganic sulfur metabolism, which culminated in a drastic reduction of the ATP and NADPH cellular levels and in higher oxidative stress. Importantly, the down-regulation of SCONC resulted in a decreased virulence of P. brasiliensis, as validated in an in vivo model of infection. Overall, our findings shed light on the inability of P. brasiliensis yeast to rely on inorganic sulfur compounds, correlating its metabolism with cellular energy and redox imbalances. Furthermore, the data herein presented reveal SconCp as a novel virulence determinant of P. brasiliensis.

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Section: Discussionmentioning

confidence: 66%

P. brasiliensis Virulence Is Affected by SconC, the Negative Regulator of Inorganic Sulfur Assimilation

et al. 2013

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“…Although A. nidulans is a widely used filamentous fungus model organism with its whole genome sequenced and annotated [33] the number of functionally characterized proteins related to GSH metabolism and transport is surprisingly low (Figure 1, Supplementary Table S-II). For example, the GlrA enzyme with GR activity plays an important role in the oxidative stress defense system of the fungus [12] and also in the reduction of cytotoxic elemental sulfur [34]. Interestingly, meanwhile GstA and GstB GSTs take part in the degradation of various toxic xenobiotics [19,34] and even in the detoxification of metals (GstA, [35]), GgtA γ-glutamyl transpeptidase is not necessary for the bulk degradation of GSH [36].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, meanwhile GstA and GstB GSTs take part in the degradation of various toxic xenobiotics [19,34] and even in the detoxification of metals (GstA, [35]), GgtA γ-glutamyl transpeptidase is not necessary for the bulk degradation of GSH [36]. Instead, the DUG pathway relying on Dug1-3 proteins is likely to be responsible for the cytosolic degradation of GSH [34]. It is worth mentioning that some genes coding for important GSH metabolism-related enzymes have only been characterized through transcriptional (dug1-3 [36]; gpxA [37]) or translational (gst3 [38]) changes.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the GlrA enzyme with GR activity plays an important role in the oxidative stress defense system of the fungus [12] and also in the reduction of cytotoxic elemental sulfur [34]. Interestingly, meanwhile GstA and GstB GSTs take part in the degradation of various toxic xenobiotics [19,34] and even in the detoxification of metals (GstA, [35]), GgtA γ-glutamyl transpeptidase is not necessary for the bulk degradation of GSH [36]. Instead, the DUG pathway relying on Dug1-3 proteins is likely to be responsible for the cytosolic degradation of GSH [34].…”

Section: Discussionmentioning

confidence: 99%

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Study on the glutathione metabolism of the filamentous fungus Aspergillus nidulans

Bakti

Király

Orosz

et al. 2017

Acta Microbiologica et Immunologica Hungarica

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Yeast protein sequence-based homology search for glutathione (GSH) metabolic enzymes and GSH transporters demonstrated that Aspergillus nidulans has a robust GSH uptake and metabolic system with several paralogous genes. In wet laboratory experiments, two key genes of GSH metabolism, gcsA, and glrA, encoding γ-L-glutamyl-L-cysteine synthetase and glutathione reductase, respectively, were deleted. The gene gcsA was essential, and the ΔgcsA mutant required GSH supplementation at considerably higher concentration than the Saccharomyces cerevisiae gsh1 mutant (8-10 mmol l −1 vs. 0.5 μmol l −1 ). In addition to some functions known previously, both genes were important in the germination of conidiospores, and both gene deletion strains required the addition of extra GSH to reach wild-type germination rates in liquid cultures. Nevertheless, the supplementation of cultures with 10 mmol l −1 GSH was toxic for the control and ΔglrA strains especially during vegetative growth, which should be considered in future development of high GSHproducer fungal strains. Importantly, the ΔglrA strain was characterized by increased sensitivity toward a wide spectrum of osmotic, cell wall integrity and antimycotic stress conditions in addition to previously reported temperature and oxidative stress sensitivities. These novel phenotypes underline the distinguished functions of GSH and GSH metabolic enzymes in the stress responses of fungi.

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“…Glrs belong to the oxidoreductase family, which is featured by a NADPH binding site, an FAD prosthetic group and an active site containing redox-active disulfi de (Mustacich and Powis 2000 ). Deletion of glutathione reductase in Fusarium oxysporum (Sato et al 2011 ), A. nidulans (Sato et al 2009(Sato et al , 2011, S. cerevisiae (Muller 1996 ) or S. pombe (Lee et al 1997 ) resulted in increased accumulation of GSSG and reduced growth rates in the presence of oxidants, ROS or elemental sulfur. In B. cinerea two glutathione reductases (BcGlr1, BcGlr2) were identifi ed.…”

Section: The Glutathione Systemmentioning

confidence: 98%

Reactive Oxygen Species in the Botrytis – Host Interaction

Siegmund

Viefhues

2015

Botrytis – The Fungus, the Pathogen and Its Management in Agricultural Systems

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Reactive oxygen species (ROS) are unavoidable byproducts of several metabolic processes. Due to their high reactivity they can cause molecular damages such as protein oxidations or DNA mutations, but they also serve as important signalling molecules within cells. Intracellular ROS primarily originate in the mitochondria; however enzymatic ROS generating systems such as the membrane associated NADPH oxidase complex (Nox) contribute to their production. In particular, during host-pathogen interactions ROS are of key importance for plant defence but also for fungal attack. As an early response to pathogen infestation the plant releases high amounts of reactive oxygen species to counteract the pathogen, known as the oxidative burst. It was shown that Botrytis exploits this plant defence reaction and even contributes to this oxidative burst by forming its' own ROS. Thus, the fungus needs a robust oxidative stress responsive (OSR) system to cope with ROS. In order to balance the intracellular redox state, effective antioxidant systems, including the thioredoxin and the glutathione system, are indispensable. Furthermore, catalases, superoxide dismutases and several peroxidases support ROS scavenging by enzymatic inactivation. Transcription factors such as the Botrytis activator protein (Bap1) and the response regulator Skn7 were shown to be involved in OSR. In this chapter we discuss the role of ROS in Botrytis -host interaction and both ROS generating and detoxifying systems and their importance for Botrytis pathogenicity. Keywords ROS • NADPH oxidases • Thioredoxin • Glutathione • Oxidative stress Reactive Oxygen Species (ROS)Reactive oxygen species (ROS) are generated in all aerobic environments and play a major role for all organisms dependent on oxygen. The oxygen in our atmosphere facilitated the evolution of multi-cellular organisms, but is also the source for several

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Glutathione Reductase/Glutathione Is Responsible for Cytotoxic Elemental Sulfur Tolerance via Polysulfide Shuttle in Fungi

Cited by 40 publications

References 42 publications

P. brasiliensis Virulence Is Affected by SconC, the Negative Regulator of Inorganic Sulfur Assimilation

P. brasiliensis Virulence Is Affected by SconC, the Negative Regulator of Inorganic Sulfur Assimilation

Study on the glutathione metabolism of the filamentous fungus Aspergillus nidulans

Reactive Oxygen Species in the Botrytis – Host Interaction

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