Interplay between acetylation and ubiquitination of imitation switch chromatin remodeler Isw1 confers multidrug resistance in Cryptococcus neoformans
- Northeastern University, China
- Chinese Academy of Medical Sciences & Peking Union Medical College, China
- The First Affiliated Hospital of China Medical University, China
- Southwest University, China
- Louisiana State University Health Sciences Center New Orleans, United States
Abstract
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. .
Data availability
The raw Isw1 proteome modification mass spectrometric data have been deposited to the Proteome Xchange (https://www.ebi.ac.uk/pride) with identifier PXD037150 (username: reviewer_pxd037150@ebi.ac.uk, password: flU9d0tA). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the iProX partner repository (Chen T, 2022) with the dataset identifier PXD045338. The transcriptomics data (RNA-seq) is deposited in NCBI's Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) and can be accessed through GEO Series accession ID GEO:GSE217187 and GSE235148. Any other data necessary to support the conclusions of this study are available in the supplementary data files and source data. Reagents and fungal strains are available from the authors upon request.
Article and author information
Author details
Funding
National Key Research and Development Program of China (2022YFC2303000)
- Chen Ding
National Natural Science Foundation of China (31870140)
- Chen Ding
Liaoning Revitalization Talents Program (XLYC1807001)
- Chen Ding
National Institutes of Health (AI156254)
- Ping Wang
National Institutes of Health (AI168867)
- Ping Wang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Detlef Weigel, Max Planck Institute for Biology Tübingen, Germany
Ethics
Animal experimentation: All animal experiments were reviewed and ethically approved by the Research Ethics Committees of the National Clinical Research Center for Laboratory Medicine of the First Affiliated Hospital of China Medical University (KT2022284) and were carried out in accordance with the regulations in the Guide for the Care and Use of Laboratory Animals issued by the Ministry of Science and Technology of the People's Republic of China. Infections with C. neoformans were performed via the intranasal route. Four- to six-week-old female Balb/c mice were purchased from Changsheng Biotech (Liaoning, China) and used for survival and fungal burden analyses.
Version history
- Received: December 21, 2022
- Preprint posted: December 30, 2022 (view preprint)
- Accepted: January 21, 2024
- Accepted Manuscript published: January 22, 2024 (version 1)
- Version of Record published: February 1, 2024 (version 2)
Copyright
© 2024, Meng et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Interplay between acetylation and ubiquitination of imitation switch chromatin remodeler Isw1 confers multidrug resistance in Cryptococcus neoformans
eLife 13:e85728.
https://doi.org/10.7554/eLife.85728
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