Ontology highlight
ABSTRACT:
PROVIDER: PRJNA885583 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21763240_1.fastq.gz | Fastqsanger.gz | |||
| SRR21763240_2.fastq.gz | Fastqsanger.gz | |||
| SRR21763241_1.fastq.gz | Fastqsanger.gz | |||
| SRR21763241_2.fastq.gz | Fastqsanger.gz | |||
| SRR21763242_1.fastq.gz | Fastqsanger.gz |
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Project description:Proteasome-dependent truncation of the negative heterochromatin regulator Epe1 mediates antifungal resistance
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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.
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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.
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Project description:The frequent use of antifungal agents has contributed to the emergence of previously rare or unidentified drug-resistant fungal species, such as Candida auris, which presents mortality rates exceeding 40% and antifungal resistance rates surpassing 90%. The rise of life-threatening infections caused by these increasingly drug-resistant fungal pathogens, coupled with the limited arsenal of effective antifungal agents, necessitates the urgent development of novel strategies to combat multidrug resistance. In this study, we systematically evaluated the role of post-translational modifications (PTMs) of histone H3 in drug resistance in C. auris, focusing on acetylation mediated by the acetyltransferases Gcn5 and Rtt109, as well as methylation by the methyltransferases Set1, Set2, and Dot1. Mutants deficient in these enzymes exhibited varying degrees of antifungal drug sensitivity. Notably, we discovered that GCN5 depletion and the subsequent loss of histone H3 acetylation downregulate key genes involved in ergosterol biosynthesis and drug efflux, resulting in increased susceptibility to major antifungal classes such as azoles and polyenes. Additionally, Gcn5 regulates cell wall integrity and echinocandin resistance through modulation of the calcineurin signaling pathway and the transcription factor Cas5. In invasive infection models using Galleria mellonella and immunocompromised mice, the deletion of GCN5 significantly reduced the virulence of C. auris. Furthermore, we demonstrated that the Gcn5 inhibitor CPTH2, when combined with the antifungal drug caspofungin (CAS), exhibits a synergistic effect against C. auris in both in vitro and in vivo models without significant toxicity to human cells or mice. In conclusion, these findings highlight the critical role of Gcn5 in the resistance and pathogenicity of C. auris, positioning it as a promising therapeutic target for combating invasive fungal infections.
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Project description:Antifungal susceptibility profiles and drug resistant mechanisms of clinical Candida catenulata isolates
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