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Interplay between acetylation and ubiquitination of Isw1 confers multidrug resistance in Cryptococcus neoformans

ABSTRACT: Cryptococcus neoformans poses a great threat to human communities, given that it quickly becomes resistant to available antifungal drugs. Herein, a conserved chromatin remodeler, Isw1, is shown to function as a master transcriptional modulator of genes responsible for multidrug resistance. It reciprocally controls drug resistance, and cells with disrupted ISW1 demonstrate profound resistance to fluconazole, ketoconazole, 5-fluorocytosine and 5-fluorouracil. Mass spectrometry reveals that Isw1 is both acetylated and ubiquitinated. These two protein posttranslational modifications confer an interplay regulation mechanism that controls Isw1 protein degradation via a ubiquitin-mediated proteasome and, consequently, C. neoformans resistance to drugs. Functional mutagenesis analysis of acetylation and ubiquitination sites reveals that the acetylation status of the lysine 97 residue on Isw1 coordinates its ubiquitination processes at lysines 113 and 441 by modulating the protein interactions between Isw1 and Cdc4, an E3 ligase. Clinical C. neoformans isolates overexpressing the undegradable ISW1 mutant demonstrate impaired drug-resistant phenotypes. Collectively, our studies reveal a sophisticated acetylation-Isw1-ubiquintation regulation axis that controls multidrug resistance in fungal pathogens.

ORGANISM(S): Cryptococcus neoformans var. grubii H99

PROVIDER: GSE217187 | GEO | 2022/11/10

REPOSITORIES: GEO

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Interplay between acetylation and ubiquitination of Isw1 confers multidrug resistance in Cryptococcus neoformans

Project description:Cryptococcus neoformans poses a great threat to human communities, given that it quickly becomes resistant to available antifungal drugs. Herein, a conserved chromatin remodeler, Isw1, is shown to function as a master transcriptional modulator of genes responsible for multidrug resistance. It reciprocally controls drug resistance, and cells with disrupted ISW1 demonstrate profound resistance to fluconazole, ketoconazole, 5-fluorocytosine and 5-fluorouracil. Mass spectrometry reveals that Isw1 is both acetylated and ubiquitinated. These two protein posttranslational modifications confer an interplay regulation mechanism that controls Isw1 protein degradation via a ubiquitin-mediated proteasome and, consequently, C. neoformans resistance to drugs. Functional mutagenesis analysis of acetylation and ubiquitination sites reveals that the acetylation status of the lysine 97 residue on Isw1 coordinates its ubiquitination processes at lysines 113 and 441 by modulating the protein interactions between Isw1 and Cdc4, an E3 ligase. Clinical C. neoformans isolates overexpressing the undegradable ISW1 mutant demonstrate impaired drug-resistant phenotypes. Collectively, our studies reveal a sophisticated acetylation-Isw1-ubiquintation regulation axis that controls multidrug resistance in fungal pathogens.

2023-06-20 | GSE235148 | GEO

Interplay between acetylation and ubiquitination of Isw1 confers multidrug resistance in Cryptococcus neoformans

Project description:Lysine acetylation and ubiquitination are one of many protein modifications and play a crucial role in the biological regulation of many organisms, but little is known about the relationship between acetylation and ubiquitination few. Here, the Isw1 protein is an important member of the chromatin remodeling complex, and we performed single-protein modification mass spectrometry detection of the C. neoformans Isw1 protein and site mutations for both detected modifications. The data showed that the two modifications of Cryptococcus neoformans Isw1 protein have a balance of each other. Acetylation can maintain protein stability and maintain protein function, while ubiquitination can reduce protein level and maintain Isw1 protein expression. The expression level of Isw1 protein leads to resistance to antifungal drugs. These results reveal the resistance mechanism of Isw1 protein of Cryptococcus neoformans to antifungal drugs.

2022-12-26 | PXD037150 | Pride

Interplay between acetylation and ubiquitination of Isw1 confers multidrug resistance in Cryptococcus neoformans

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Interplay between acetylation and ubiquitination of Isw1 confers multidrug resistance in Cryptococcus neoformans

Project description:Interplay between acetylation and ubiquitination of Isw1 confers multidrug resistance in Cryptococcus neoformans

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Interplay between acetylation and ubiquitination of Isw1 confers multidrug resistance in Cryptococcus neoformans

Project description:Interplay between acetylation and ubiquitination of Isw1 confers multidrug resistance in Cryptococcus neoformans

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Novel genetic mutations in pyrimidine salvage pathway enzymes from Cryptococcus neoformans contribute to reduced susceptibility against 5-fluorocytosine

Project description:The most common cause of cryptococcal meningitis is Cryptococcus neoformans. The addition of 5-fluorocytosine to the treatment of patient with this potentially fatal infection significantly improves disease outcome. However, developing resistance to this drug is a serious problem in patient management. In this study, we investigated the molecular mechanisms causing 5-FC resistance in three clinical isolates of C. neoformans using genomic and proteomic approaches. Our findings show that genetic alterations in genes involved in the pyrimidine salvage pathway caused 5-FC resistance in these isolates. Specifically, one isolate had a missense mutation (E64G) in the uracil phosphoribosyl transferase gene (FUR1), another isolate had a large deletion spanning the cytosine deaminase gene (FCY1), and the third isolate had a point mutation in the same gene leading to a truncated protein at amino acid 164 (STOPW164*). Proteomic data confirmed that the genetic changes led to the absence or decreased the amount of the enzymes in the 5-FC resistant isolates. Transformation experiments confirmed that the genetic changes ultimately affected 5-FC susceptibility, providing further evidence of the effect of the genetic changes on 5-FC susceptibility.

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Antifungal activity of the repurposed drug disulfiram against Cryptococcus neoformans.

Project description:Fungal infections have become a clinical challenge due to the emergence of drug-resistance of invasive fungi and a rapid increase of novel pathogens. The development of drug resistance has further restricted the use of antifungal agents. Therefore, there is anurgentneedto searchforalternativetreatmentoptions for Cryptococcus neoformans (C. neoformans). Disulfiram (DSF) has a high human safety profile and promising applications as an antiviral, antifungal, antiparasitic, and anticancer agent. In contrast, the effect of DSF on Cryptococcus has yet to be thoroughly researched. This study investigated the antifungal effect and mechanism of DSF againstC. neoformansto provide a new theoretical foundation for treating Cryptococcal infections. In vitro studies demonstrated that DSF inhibitedCryptococcusat minimum inhibitory concentrations (MICs) ranging from 1.0 to 8.0 μg/mL. Combined antifungal effects were also observed with 5-fluorocytosine, amphotericin B, terbinafine, or ketoconazole. In vivo, DSF exerted asignificantprotectiveeffectforGalleria mellonella infected with C. neoformans.Mechanistic investigations showed that DSF dose-dependently inhibited the melanin, urease, acetaldehyde dehydrogenase, capsule, and biofilm formation or viability ofC. neoformans.Further study indicated DSF affectedC. neoformansby interfering with multiple biological pathways, including replication, metabolism, membrane transport, and biological enzyme activity. Potentially essential targets of these pathways included acetaldehyde dehydrogenase, catalase, ATP-binding cassette transporter (ABC transporter) AFR2, and iron-sulfur cluster transporter ATM1. These findings contribute to the understanding of mechanisms inC. neoformans, and provide new insights for the application of DSF.

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A genome-wide transcriptomic analysis of radiation-responsive genes in the radiation-resistant fungus, C. neoformans

Project description:The basidiomycetous fungus Cryptococcus has been known as radiation resistant fungi and is found in highly radioactive environments such as the damaged nuclear reactor at Chernobyl. Although Cryptococcus exhibits greater resistant for gamma radiation than the model yeast Saccharomyces cerevisiae, the resistant mechanism of gamma radiation remains elusive. To elucidate a unique regulatory system for radiation-resistance in C. neoformans, we performed genome-wide comparative analysis through DNA microarray analysis using C. neoformans WT strain (serotype A, H99 strain) responding gamma radiation. Based on the transcriptome analysis, genes involved in DNA damage repair systems (RAD51, RDH54, and RAD54) were significantly increased in response to gamma radiation. Actually, rad54â?? and rdh54â?? mutants exhibited sensitivity against both gamma radiation and DNA damage inducers. Furthermore, genes regarding to molecular chaperone and ubiquitination systems were strongly induced. In contrast, expression levels of genes related to protein synthesis, fatty acids/sterols synthesis, and other cellular molecules. Especially, ergosterol homeostasis is required for gamma radiation resistance. Furthermore, radiation-induced genes such as RIG4, RIG5, and RIG6 in C. neoformans play critical roles in gamma radiation resistance. Taken together, the transcriptome analysis contributes to understanding unique molecular mechanism of radiation-resistant fungus C. neoformans. To elucidate transcriptome change during recovery process post irrdiation, samples were taken at three time interval (30 min, 60 min, and 120 min). The three independent DNA microarry with three independent biological replicates were analyzed to obtain high reliability.

2016-06-01 | E-GEOD-80230 | biostudies-arrayexpress

A genome-wide transcriptomic analysis of radiation-responsive genes in the radiation-resistant fungus, C. neoformans

Project description:The basidiomycetous fungus Cryptococcus has been known as radiation resistant fungi and is found in highly radioactive environments such as the damaged nuclear reactor at Chernobyl. Although Cryptococcus exhibits greater resistant for gamma radiation than the model yeast Saccharomyces cerevisiae, the resistant mechanism of gamma radiation remains elusive. To elucidate a unique regulatory system for radiation-resistance in C. neoformans, we performed genome-wide comparative analysis through DNA microarray analysis using C. neoformans WT strain (serotype A, H99 strain) responding gamma radiation. Based on the transcriptome analysis, genes involved in DNA damage repair systems (RAD51, RDH54, and RAD54) were significantly increased in response to gamma radiation. Actually, rad54∆ and rdh54∆ mutants exhibited sensitivity against both gamma radiation and DNA damage inducers. Furthermore, genes regarding to molecular chaperone and ubiquitination systems were strongly induced. In contrast, expression levels of genes related to protein synthesis, fatty acids/sterols synthesis, and other cellular molecules. Especially, ergosterol homeostasis is required for gamma radiation resistance. Furthermore, radiation-induced genes such as RIG4, RIG5, and RIG6 in C. neoformans play critical roles in gamma radiation resistance. Taken together, the transcriptome analysis contributes to understanding unique molecular mechanism of radiation-resistant fungus C. neoformans.

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Transcriptomics analysis of amphotericin B and lactoferrin drug synergy in Cryptococcus neoformans H99

Project description:Invasive fungal infections (IFIs) are difficult to treat. Few effective antifungal drugs are available and many have problems with toxicity, efficacy and drug-resistance. To overcome these challenges, existing therapies may be enhanced using more than one agent acting in synergy. Previously, we have found amphotericin B (AMB) and the iron chelator, lactoferrin (LF), were synergistic against Cryptococcus neoformans and Saccharomyces cerevisiae. This study investigates the mechanism of AMB+LF synergy using RNA-seq in Cryptococcus neoformans H99.

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