Susceptibility to Medium-Chain Fatty Acids Is Associated with Trisomy of Chromosome 7 in
            <i>Candida albicans</i>

Ma, Qinxi; Ola, Mihaela; Iracane, Elise; Butler, Geraldine

doi:10.1128/msphere.00402-19

Cited by 9 publications

(4 citation statements)

References 41 publications

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“…Our sequencing confirmed a previous report from the Butler lab showing that SN152 contains a large loss of heterozygosity (LOH) region on chromosome 2 and also a smaller LOH region on chromosome 3 [ Fig. 5 and reference ( 49 )]. These LOH events were inherited from the strain used to make SN152 ( 50 ).…”

Section: Resultssupporting

confidence: 90%

The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans

Lo,

Wang,

Nickson

et al. 2024

mSphere

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Fungal infections cause a large health burden but are treated by only a handful of antifungal drug classes. Chromatin factors have emerged as possible targets for new antifungals. These targets include the reader proteins, which interact with posttranslationally modified histones to influence DNA transcription and repair. The YEATS domain is one such reader recognizing both crotonylated and acetylated histones. Here, we performed a detailed structure/function analysis of the Candida albicans YEATS domain reader Yaf9, a subunit of the NuA4 histone acetyltransferase and the SWR1 chromatin remodeling complex. We have previously demonstrated that the homozygous deletion mutant yaf9Δ/Δ displays growth defects and is avirulent in mice. Here we show that a YEATS domain mutant expected to inactivate Yaf9’s chromatin binding does not display strong phenotypes in vitro , nor during infection of immune cells or in a mouse systemic infection model, with only a minor virulence reduction in vivo . In contrast to the YEATS domain mutation, deletion of the C-terminal domain of Yaf9, a protein–protein interaction module necessary for its interactions with SWR1 and NuA4, phenocopies the null mutant. This shows that the C-terminal domain is essential for Yaf9 roles in vitro and in vivo , including C. albicans virulence. Our study informs on the strategies for therapeutic targeting of Yaf9, showing that approaches taken for the mammalian YEATS domains by disrupting their chromatin binding might not be effective in C. albicans , and provides a foundation for studying YEATS proteins in human fungal pathogens. IMPORTANCE The scarcity of available antifungal drugs and rising resistance demand the development of therapies with new modes of action. In this context, chromatin regulation may be a target for novel antifungal therapeutics. To realize this potential, we must better understand the roles of chromatin regulators in fungal pathogens. Toward this goal, here, we studied the YEATS domain chromatin reader Yaf9 in Candida albicans . Yaf9 uses the YEATS domain for chromatin binding and a C-terminal domain to interact with chromatin remodeling complexes. By constructing mutants in these domains and characterizing their phenotypes, our data indicate that the Yaf9 YEATS domain might not be a suitable therapeutic drug target. Instead, the Yaf9 C-terminal domain is critical for C. albicans virulence. Collectively, our study informs how a class of chromatin regulators performs their cellular and pathogenesis roles in C. albicans and reveals strategies to inhibit them.

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Section: Resultssupporting

confidence: 90%

The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans

Lo,

Wang,

Nickson

et al. 2024

mSphere

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“…C. albicans strains passaged in the mouse GI repeatedly evolved trisomies for chromosome 7, which resulted in increased fitness for this niche [19]. This aneuploidy was later implicated in susceptibility to medium chain fatty acids [43]. Oxidative metabolism may also be under strong selection within the host.…”

Section: Microevolution In Complex Host Environmentsmentioning

confidence: 99%

Short-term evolution strategies for host adaptation and drug escape in human fungal pathogens

Beekman

Ene

2020

PLoS Pathog

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Research on human fungal pathogens has historically taken a backseat to other infectious diseases, perhaps due to a common misperception that fungi largely cause superficial infections [1]. In reality, fungi can be life-threatening to those who become immunocompromised during medical procedures or through conditions such as HIV and diabetes. Invasive fungal infections are estimated to kill over 1 million people every year, with mortality rates reaching 50% [2]. Significant challenges to the treatment of fungal infections include the limited availability of antifungals and the innate ability of fungi to rapidly evolve and adapt to fluctuating conditions. This adaptive ability is partially driven by extensive genomic plasticity, with many species acquiring diverse ploidy states, chromosomal rearrangements, and point mutations during host colonization [3-8]. Genetic plasticity enables rapid increases in virulence and antifungal drug resistance, which often translate to poor disease outcomes. Short-term evolution (microevolution) strategies in fungal pathogens are therefore essential for environmental adaptation in the mammalian host, and their study can inform adaptive mechanisms in other eukaryotes. Ploidy shifts enable rapid fitness jumps under stressful conditions Many clinically relevant fungi display dynamic changes in ploidy, including both karyotypic variations (number of sets of chromosomes) as well as aneuploidy (imbalance in chromosome copy number). Some fungal pathogens exist as stable haploid, diploid, or polyploid cells, but ploidy can change upon shifting conditions. Alterations in baseline ploidy have been described for some of the most prevalent genera (Candida, Cryptococcus, and Aspergillus) and are often selected for in the host or during antifungal treatment. Extra chromosomes are common in isolates from human infections [5, 6, 8, 9] and after passage through mammalian hosts during experimental microevolution [10-12]. Under nutrient starvation, Candida albicans isolates can favor either near-haploid or near-diploid states, indicating that karyotypic reduction can provide an efficient adaptive route in some conditions [13]. Aneuploidy is also common in C. albicans and in Cryptococcus neoformans lineages and has been linked to increased virulence and drug resistance [14] [15]. Chromosomal duplication can mediate adaptation through gene dosage, as transcript levels are often proportional to gene copy number [16]. This can be seen in both C. albicans and Cryptococcus species, for which antifungal treatment selects for increased copies of chromosomes or chromosomal segments containing drug targets and/or efflux pumps. Thus, clinical isolates of Cryptococcus lineages VNI and VGI that persisted during fluconazole therapy were frequently disomic for chromosome 1 [5]. Analogous in vitro fluconazole treatment of Cryptococcus lineages VNI and VNIV selected for disomy of

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“…The copyright holder for this preprint this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.06.471441 doi: bioRxiv preprint sequenced the genome of 3 randomly selected ulp2 Δ/Δ colonies by whole genome sequencing (WGS) and compared their genome sequences to the C. albicans reference genome. This analysis demonstrates that deletion of C. albicans ULP2 does not select for specific chromosome rearrangements and identifies different genomic variations that are not present in the parental WT strain (Fig 3D and Table S2) [85]. While deletion of ULP2 leads to very few (<10) de novo mutations (Table S2), two of the three colonies underwent extensive LOH on different chromosomes (Fig 3D and Table S2).…”

Section: Loss Of Ulp2 Leads To Increased Genome Instabilitymentioning

confidence: 82%

The SUMO protease Ulp2 regulates genome stability and drug resistance in the human fungal pathogen Candida albicans

Rizzo

Soisangwan

Soetaert

et al. 2021

Preprint

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Stress-induced genome instability in microbial organisms is emerging as a critical regulatory mechanism for driving rapid and reversible adaption to drastic environmental changes. In Candida albicans, a human fungal pathogen that causes life-threatening infections, genome plasticity confers increased virulence and antifungal drug resistance. Discovering the mechanisms regulating C. albicans genome plasticity is a priority to understand how this and other microbial pathogens establish life-threatening infections and develop resistance to antifungal drugs. We identified the SUMO protease Ulp2 as a critical regulator of C. albicans genome integrity through genetic screening. Deletion of ULP2 leads to hypersensitivity to genotoxic agents and increased genome instability. This increased genome diversity causes reduced fitness under standard laboratory growth conditions but enhances adaptation to stress, making ulp2Δ/Δ cells more likely to thrive in the presence of antifungal drugs. Whole-genome sequencing indicates that ulp2Δ/Δ cells counteract antifungal drug-induced stress by developing segmental aneuploidies of chromosome R and chromosome I. We demonstrate that intrachromosomal repetitive elements drive the formation of complex novel genotypes with adaptive power.

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Susceptibility to Medium-Chain Fatty Acids Is Associated with Trisomy of Chromosome 7 in Candida albicans

Cited by 9 publications

References 41 publications

The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans

The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans

Short-term evolution strategies for host adaptation and drug escape in human fungal pathogens

The SUMO protease Ulp2 regulates genome stability and drug resistance in the human fungal pathogen Candida albicans

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