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| Status |
Public on Nov 10, 2022 |
| Title |
Interplay between acetylation and ubiquitination of Isw1 confers multidrug resistance in Cryptococcus neoformans |
| Organism |
Cryptococcus neoformans var. grubii H99 |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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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| Overall design |
Performed paired-end RNA-seq of Cryptococcus neoformans H99s as Control group and isw1∆ strains as in 50ml YPD broth at OD600=0.8 with 10μg/ml FLC, respectively in biological triplicates.
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| |
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| Contributor(s) |
Ding C |
| Citation(s) |
38251723 |
| |
| Submission date |
Nov 03, 2022 |
| Last update date |
Feb 14, 2024 |
| Contact name |
Yang Meng |
| E-mail(s) |
mm13940381361@gmail.com
|
| Organization name |
Northeastern University
|
| Department |
College of Life and Health Sciences
|
| Street address |
Wenhua street num 11
|
| City |
shenyang |
| ZIP/Postal code |
110819 |
| Country |
China |
| |
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| Platforms (1) |
| GPL28230 |
HiSeq X Ten (Cryptococcus neoformans var. grubii H99) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA897880 |
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