Differential Roles of a Family of Flavodoxin-Like Proteins That Promote Resistance to Quinone-Mediated Oxidative Stress in Candida albicans

Foderaro, Jenna E.; Konopka, James B.

doi:10.1128/iai.00670-20

“…The FLP Pst2 affects the survival in stationary phase 55 , but the mechanism remained unknown. Our results are consistent with the high abundance of eisosomes in quiescent conidiospores and ascospores of Aspergillus nidulans 56,57 , the peroxidation-protective roles and the increased levels of ubiquinol in stationary phase 40,41,58 , and the known antioxidant roles of FLPs in Candida albicans against exogenous quinones and PUFAs 42,59 .…”

Section: Discussionsupporting

confidence: 87%

Ferroptosis-Protective Membrane Domains in Quiescence

Megarioti

¹

,

Αθανασόπουλος

²

,

Koulouris

³

et al. 2023

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Quiescence is a common cellular state, required for stem-cell maintenance and microorganismal survival under stress conditions or starvation. However, the mechanisms promoting quiescence maintenance remain poorly known. Plasma membrane components segregate into distinct microdomains, yet the role of this compartmentalization in quiescence remains unexplored. Here, we show that Flavodoxin-like proteins (FLPs), ubiquinone reductases of the yeast eisosome membrane compartment, protect quiescent cells from lipid peroxidation and ferroptosis. Eisosomes and FLPs expand specifically in respiratory-active quiescent cells, and mutants lacking either show accelerated aging, defective quiescence maintenance, and accumulate peroxidized phospholipids with monounsaturated or polyunsaturated fatty acids (PUFA). FLPs are essential for the extra-mitochondrial regeneration of the lipophilic antioxidant ubiquinol. FLPs, alongside the Gpx1/2/3 glutathione peroxidases, prevent iron-driven, PUFA-dependent ferroptotic cell death. Our work is the first description of ferroptosis-protective mechanisms in yeast and introduces plasma membrane compartmentalization as an important factor for the long-term survival of quiescent cells.

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“…However, the Q Mut, which lacks all four FLPs (pst1Δ/pst2Δ/pst3Δ/ycp4Δ) as well as ZTA1, exhibited greater susceptibility to TBBQ, although not to BZQ or MEN. One possibility for this specific susceptibility is that TBBQ, being the most non-polar quinone tested in our study (8), may cross the plasma membrane more readily and enter the cytoplasm where Zta1 is located (Fig. 2).…”

Section: Discussionmentioning

confidence: 97%

“…The FLPs are localized to specialized plasma membrane domains called eisosomes, which is thought to facilitate a role in protecting the C. albicans plasma membrane polyunsaturated fatty acids (PUFAs) which are more prone to lipid peroxidation. This type of lipid oxidation can trigger a chain reaction that spreads to other PUFAs and then the peroxidized lipids can damage proteins and DNA (8, 29). Another QOR present in fungi is the ζ-crystallin-like protein Zta1, which belongs to a structurally distinct family that is believed to catalyze a one-electron reduction of quinones (16, 18).…”

Section: Discussionmentioning

confidence: 99%

“…FLPs are enriched in plasma membrane eisosome domains where they are thought to protect the C. albicans plasma membrane by reducing ubiquinone to ubiquinol so that it can reduce reactive oxygen species (7). FLPs are also important for resisting oxidative stress caused by treatment of C. albicans with a variety of smaller quinone molecules (7,8). FLPs are thought to therefore play a critical role in protecting cells from quinones that are created as secondary metabolites, or in many cases are used by plants and insects as defense molecules (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

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TheCandida albicansζ-crystallin homolog Zta1 promotes resistance to oxidative stress

Gandra,

Johnson,

Nett

et al. 2023

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The fungal pathogen Candida albicans is capable of causing lethal infections in humans. Its pathogenic potential is due in part to the ability to resist various stress conditions in the host, including oxidative stress. Recent studies showed that a family of four flavodoxin-like proteins (Pst1, Pst2, Pst3, Ycp4) that function as quinone reductases promotes resistance to oxidation and is needed for virulence. Therefore, in this study Zta1 was examined because it belongs to a structurally distinct family of quinone reductases that are highly conserved in eukaryotes and have been called the ζ-crystallins. The levels of Zta1 in C. albicans rapidly increased after exposure to oxidants, consistent with a role in resisting oxidative stress. Accumulation of reactive oxygen species was significantly higher in cells lacking ZTA1 upon exposure to quinones and other oxidants. Furthermore, deletion ofZTA1in a mutant lacking the four flavodoxin-like proteins, resulted in further increased susceptibility to quinones, indicating that these distinct quinone reductases work in combination. These results demonstrate that Zta1 contributes toC. albicanssurvival after exposure to oxidative conditions, which increases the understanding of howC. albicansresists stressful conditions in the host.

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“…Recently, a new antioxidant pathway was described in C. albicans involving four flavodoxin-like proteins (FLPs; Pst1, Pst2, Pst3, and Ycp4) that are important for resisting oxidative stress, preventing lipid peroxidation, and for virulence in mice ( 7 , 8 ). The FLPs belong to a large family of NADPH:quinone oxidoreductases that are present in many organisms, including bacteria, fungi, and plants, but are not conserved in mammals ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

The Candida albicans ζ-crystallin homolog Zta1 promotes resistance to oxidative stress

Gandra,

Johnson,

Nett

et al. 2023

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The fungal pathogen Candida albicans is capable of causing lethal infections in humans. Its pathogenic potential is due in part to the ability to resist various stress conditions in the host, including oxidative stress. Recent studies showed that a family of four flavodoxin-like proteins (Pst1, Pst2, Pst3, Ycp4) that function as quinone reductases promotes resistance to oxidation and is needed for virulence. Therefore, in this study, Zta1 was examined because it belongs to a structurally distinct family of quinone reductases that are highly conserved in eukaryotes and have been called the ζ-crystallins. The levels of Zta1 in C. albicans rapidly increased after exposure to oxidants, consistent with a role in resisting oxidative stress. Accumulation of reactive oxygen species (ROS) was significantly higher in cells lacking ZTA1 upon exposure to quinones and other oxidants. Furthermore, the deletion of ZTA1 in a mutant lacking the four flavodoxin-like proteins, resulted in further increased susceptibility to quinones, indicating that these distinct quinone reductases work in combination. These results demonstrate that Zta1 contributes to C. albicans survival after exposure to oxidative conditions, which increases the understanding of how C. albicans resist stressful conditions in the host. IMPORTANCE Candida albicans is an important human pathogen that can cause lethal systemic infections. The ability of C. albicans to colonize and establish infections is closely tied to its highly adaptable nature and capacity to resist various types of stress, including oxidative stress. Previous studies showed that four C. albicans proteins belonging to the flavodoxin-like protein family of quinone reductases are needed for resistance to quinones and virulence. Therefore, in this study, we examined the role of a distinct type of quinone reductase, Zta1, and found that it acts in conjunction with the flavodoxin-like proteins to protect against oxidative stress.

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Differential Roles of a Family of Flavodoxin-Like Proteins That Promote Resistance to Quinone-Mediated Oxidative Stress in Candida albicans

Cited by 8 publications

References 70 publications

Ferroptosis-Protective Membrane Domains in Quiescence

Ferroptosis-Protective Membrane Domains in Quiescence

TheCandida albicansζ-crystallin homolog Zta1 promotes resistance to oxidative stress

The Candida albicans ζ-crystallin homolog Zta1 promotes resistance to oxidative stress

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