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

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

PROVIDER: PRJNA984671 | ENA |

REPOSITORIES: ENA

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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

2022-11-10 | GSE217187 | 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

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

| PRJNA897880 | ENA

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

2023-09-13 | PXD045338 |

Interplay between acetylation and ubiquitination of imitation switch chromatin remodeler Isw1 confers multidrug resistance in <i>Cryptococcus neoformans</i>.

Project description:Cryptococcus neoformans poses a threat to human health, but anticryptococcal therapy is hampered by the emergence of drug resistance, whose underlying mechanisms remain poorly understood. Herein, we discovered that Isw1, an imitation switch chromatin remodeling ATPase, functions as a master modulator of genes responsible for in vivo and in vitro multidrug resistance in C. neoformans. Cells with the disrupted ISW1 gene exhibited profound resistance to multiple antifungal drugs. Mass spectrometry analysis revealed that Isw1 is both acetylated and ubiquitinated, suggesting that an interplay between these two modification events exists to govern Isw1 function. Mutagenesis studies of acetylation and ubiquitination sites revealed that the acetylation status of Isw1K97 coordinates with its ubiquitination processes at Isw1K113 and Isw1K441 through modulating the interaction between Isw1 and Cdc4, an E3 ligase. Additionally, clinical isolates of C. neoformans overexpressing the degradation-resistant ISW1K97Q allele showed impaired drug-resistant phenotypes. Collectively, our studies revealed a sophisticated acetylation-Isw1-ubiquitination regulation axis that controls multidrug resistance in C. neoformans.

| S-EPMC10834027 | biostudies-literature

Histone exchange in wildtype, isw1, chd1, isw1 chd1 and ioc4 yeast strains

Project description:Histone exchange in wildtype, isw1, chd1, isw1 chd1 and ioc4 yeast strains.

2012-07-25 | GSE32043 | GEO

An adaptive stress response that confers cellular resilience to decreased ubiquitination

Project description:An adaptive stress response that confers cellular resilience to decreased ubiquitination

| PRJNA918302 | ENA

Isw1 and Chd1 maintain chromatin organization during transcription [K56ac data]

Project description:ChIP-chip assays to determine the occupancy of acetylated histone H3 K56 in wildtype, isw1, chd1, isw1 chd1 and ISW1[K227R] yeast.

2012-07-25 | GSE36405 | GEO

Isw1 and Chd1 maintain chromatin organization during transcription [isw1 chd1 mutant expression]

Project description:Gene expression microarray experiments to determine the existence of intragenic (cryptic) transcripts in an isw1 chd1 mutant yeast strain.

2012-07-25 | GSE37158 | GEO

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