Interplay between acetylation and ubiquitination of imitation switch chromatin remodeler Isw1 confers multidrug resistance in Cryptococcus neoformans

  1. Yang Meng
  2. Yue Ni
  3. Zhuoran Li
  4. Tianhang Jiang
  5. Tianshu Sun
  6. Yanjian Li
  7. Xindi Gao
  8. Hailong Li
  9. Chenhao Suo
  10. Chao Li
  11. Sheng Yang
  12. Tian Lan
  13. Guojian Liao
  14. Tongbao Liu
  15. Ping Wang
  16. Chen Ding  Is a corresponding author
  1. Northeastern University, China
  2. Chinese Academy of Medical Sciences & Peking Union Medical College, China
  3. The First Affiliated Hospital of China Medical University, China
  4. Southwest University, China
  5. 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.

The following data sets were generated

Article and author information

Author details

  1. Yang Meng

    College of Life and Health Sciences, Northeastern University, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Yue Ni

    College of Life and Health Sciences, Northeastern University, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Zhuoran Li

    College of Life and Health Sciences, Northeastern University, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Tianhang Jiang

    College of Life and Health Sciences, Northeastern University, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Tianshu Sun

    Department of Scientific Research, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Yanjian Li

    College of Life and Health Sciences, Northeastern University, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Xindi Gao

    College of Life and Health Sciences, Northeastern University, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Hailong Li

    NHC Key Laboratory of AIDS Immunology, The First Affiliated Hospital of China Medical University, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Chenhao Suo

    College of Life and Health Sciences, Northeastern University, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Chao Li

    College of Life and Health Sciences, Northeastern University, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Sheng Yang

    College of Life and Health Sciences, Northeastern University, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Tian Lan

    College of Life and Health Sciences, Northeastern University, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Guojian Liao

    College of Pharmaceutical Sciences, Southwest University, Chongqing, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Tongbao Liu

    Medical Research Institut, Southwest University, Chongqing, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Ping Wang

    Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center New Orleans, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Chen Ding

    College of Life and Health Sciences, Northeastern University, Shenyang, China
    For correspondence
    dingchen@mail.neu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9195-2255

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

  1. 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

  1. Received: December 21, 2022
  2. Preprint posted: December 30, 2022 (view preprint)
  3. Accepted: January 21, 2024
  4. Accepted Manuscript published: January 22, 2024 (version 1)
  5. 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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  1. Yang Meng
  2. Yue Ni
  3. Zhuoran Li
  4. Tianhang Jiang
  5. Tianshu Sun
  6. Yanjian Li
  7. Xindi Gao
  8. Hailong Li
  9. Chenhao Suo
  10. Chao Li
  11. Sheng Yang
  12. Tian Lan
  13. Guojian Liao
  14. Tongbao Liu
  15. Ping Wang
  16. Chen Ding
(2024)
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

Share this article

https://doi.org/10.7554/eLife.85728

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