Schizosaccharomyces pombe Grx4 regulates the transcriptional repressor Php4 via [2Fe–2S] cluster binding

Dlouhy, Adrienne C.; Beaudoin, Jude; Labbé, Simon; Outten, Caryn E.

doi:10.1039/c7mt00144d

Cited by 27 publications

(30 citation statements)

References 35 publications

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“…S6). In general, these results highlighted the negative impact of Grx4 on the regulation of iron-dependent functions (Table 2), similar to the influence of the monothiol glutaredoxin Grx4 with the transcription factor Php4 in S. pombe (27, 33, 34).…”

Section: Resultssupporting

confidence: 68%

“…Sl). Of note, the monothiol Grx domain with the CGFS active site motif is highly conserved and known to be required for [2Fe-2S] cluster binding and trafficking, and the regulation of iron homeostasis in fungi (24–34). The N-terminal region of Grx4 from C. neoformans also contained the WAXXC motif of the thioredoxin (TRX) domain found in monothiol glutaredoxins (24).…”

Section: Resultsmentioning

confidence: 99%

“…Grx3 and Grx4 in S. cerevisiae and Grx4 in S. pombe are known to interact with and to influence the activity of transcription factors that regulate iron homeostasis (24–34). We therefore employed the yeast two-hybrid assay to test the interaction between Grx4 and Cirl.…”

Section: Resultsmentioning

confidence: 99%

“…The glutaredoxin Grx4 in S. pombe is known to co-regulate genes for iron acquisition with Fep1, an ortholog of Cir1, and to interact with Php4, a regulator of functions that use iron (27, 29, 30, 33, 34). We therefore performed an RNA-Seq analysis to assess the impact of loss of Grx4 on the transcriptomes of C. neoformans cells grown in low and high iron conditions (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The wealth of information from model yeasts on the mechanistic details of monothiol GRXs, [2Fe-2S] cluster binding and transcriptional regulation provides a framework to interpret the contribution of Grx4 to iron sensing in C. neoformans (25–34, 43). In model yeasts, monothiol glutaredoxins play a critical role in sensing iron availability via [2Fe-2S] cluster assembly to influence the activities of transcription factors that regulate the expression of iron acquisition and iron dependent functions (25–34). For example, the monothiol glutaredoxins Grx3 and Grx4 form [2Fe-2S] cluster binding complexes with the cytosolic proteins Fra1 and Fra2 in S. cerevisiae to dissociate the activator Aft1 from the promoters of genes for iron uptake upon iron repletion.…”

Section: Discussionmentioning

confidence: 99%

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The monothiol glutaredoxin Grx4 interacts with the Cryptococcus iron regulator Cirl and regulates iron homeostasis and virulence in the Cryptococcus neoformans

Attarian

Guo

Caza

et al. 2018

Preprint

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26The acquisition of iron and the maintenance of iron homeostasis are important aspects of 27 the virulence in the pathogenic fungus Cryptococcus neoformans. In this study, we identified 28 the monothiol glutaredoxin Grx4 as a binding partner of Cir1, a master regulator of iron-29 responsive genes and virulence factor elaboration in C. neoformans. Monothiol glutaredoxins 30 are important regulators of iron homeostasis because of their conserved roles in [2Fe-2S] cluster 31 sensing and trafficking. We confirmed that Grx4 binds Cir1 and demonstrated that iron 32 repletion promotes the relocalization of Grx4 from the nucleus to the cytoplasm. Nuclear 33 retention is partially dependent on Cir1 and also influenced by treatment with the proteasome 34 inhibitor bortezomib. Cir1 remains in the nucleus in both iron replete and iron limiting 35 conditions. We also found that a grx4Δ mutant displayed iron-related phenotypes similar to 36 those of a cir1Δ mutant, including poor growth upon iron deprivation. Importantly, a grx4Δ 37 mutant was avirulent in mice, a phenotype consistent with observed defects in the key virulence 38 determinants, capsule and melanin, and poor growth at 37°C. A comparative transcriptome 39 analysis of a grx4Δ mutant and the WT strain in low iron and iron-replete conditions confirmed 40 a central role for Grx4 in iron homeostasis. Dysregulation of iron-related metabolism was 41 consistent with grx4Δ mutant phenotypes related to oxidative stress, mitochondrial function, and 42 DNA repair. Overall, the phenotypes of the grx4Δ mutant and the RNA-Seq analysis support 43 the hypothesis that Grx4 functions as a sensor of iron levels, in part through an interaction with 44 Cir1, to extensively regulate iron homeostasis and contribute to virulence. 45 46 Importance 47 48Fungal pathogens cause life-threatening diseases in humans, particularly in 49 immunocompromised people, and there is a tremendous need for a greater understanding of 50 pathogenesis to support new therapies. One prominent fungal pathogen, Cryptococcus 51 neoformans, causes menigitis in people suffering from HIV/AIDS. In the current study, we 52 focused on characterizing mechanisms by which C. neoformans senses iron availability because 53 iron is both a key nutrient and a signal for proliferation of the pathogen in vertebrate hosts. 54 Specifically, we characterized a monothiol glutaredoxin protein Grx4 that functions as a sensor 55 3 of iron, and that interacts with regulatory factors to control the ability of C. neoformans to cause 56 disease. Grx4 regulates key virulence factors and a mutant is unable to cause disease in a mouse 57 model of cryptococcosis. Overall, our study provides new insights into nutrient sensing and the 58 role of iron in the pathogenesis of fungal diseases. 59 60 61 62 63 65 meningoencephalitis in immunocompromised people including those with HIV/AIDS (1-3). 66Despite the use of highly active antiretroviral therapy (HAART), there are still ~200,000 cases 67 of cryptococcal meningoencephalitis per year, and...

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Section: Resultssupporting

confidence: 68%