1. Chromosomes and Gene Expression
  2. Microbiology and Infectious Disease

Temporal transcriptional response of Candida glabrata during macrophage infection reveals a multifaceted transcriptional regulator CgXbp1 important for macrophage response and fluconazole resistance

  1. Maruti Nandan Rai
  2. Qing Lan
  3. Chirag Parsania
  4. Rikky Rai
  5. Niranjan Shirgaonkar
  6. Ruiwen Chen
  7. Li Shen
  8. Kaeling Tan
  9. Koon Ho Wong  Is a corresponding author
  1. University of Macau, Macao
https://doi.org/10.7554/eLife.73832
Share this article
Cite this article
  1. Maruti Nandan Rai
  2. Qing Lan
  3. Chirag Parsania
  4. Rikky Rai
  5. Niranjan Shirgaonkar
  6. Ruiwen Chen
  7. Li Shen
  8. Kaeling Tan
  9. Koon Ho Wong
(2024)
Temporal transcriptional response of Candida glabrata during macrophage infection reveals a multifaceted transcriptional regulator CgXbp1 important for macrophage response and fluconazole resistance
eLife 13:e73832.
https://doi.org/10.7554/eLife.73832
  2. Download BibTeX
  3. Download .RIS

Abstract

Candida glabrata can thrive inside macrophages and tolerate high levels of azole antifungals. These innate abilities render infections by this human pathogen a clinical challenge. How C. glabrata reacts inside macrophages and what is the molecular basis of its drug tolerance are not well understood. Here, we mapped genome-wide RNA polymerase II (RNAPII) occupancy in C. glabrata to delineate its transcriptional responses during macrophage infection in high temporal resolution. RNAPII profiles revealed dynamic C. glabrata responses to macrophages with genes of specialized pathways activated chronologically at different times of infection. We identified an uncharacterized transcription factor (CgXbp1) important for the chronological macrophage response, survival in macrophages, and virulence. Genome-wide mapping of CgXbp1 direct targets further revealed its multi-faceted functions, regulating not only virulence-related genes but also genes associated with drug resistance. Finally, we showed that CgXbp1 indeed also affects fluconazole resistance. Overall, this work presents a powerful approach for examining host-pathogen interaction and uncovers a novel transcription factor important for C. glabrata's survival in macrophages and drug tolerance.

Data availability

RNAPII ChIP-seq, CgXbp1MYC ChIP-seq and RNAseq data are available from the NCBI SRA database under the accession number PRJNA665114, PRJNA743592 and PRJNA1162247, respectively.

The following data sets were generated

Article and author information

Author details

  1. Maruti Nandan Rai

    Faculty of health sciences, University of Macau, Taipa, Macao
    Competing interests
    The authors declare that no competing interests exist.

  2. Qing Lan

    Faculty of health sciences, University of Macau, Taipa, Macao
    Competing interests
    The authors declare that no competing interests exist.

  3. Chirag Parsania

    Faculty of health sciences, University of Macau, Taipa, Macao
    Competing interests
    The authors declare that no competing interests exist.

  4. Rikky Rai

    Faculty of health sciences, University of Macau, Taipa, Macao
    Competing interests
    The authors declare that no competing interests exist.

  5. Niranjan Shirgaonkar

    Faculty of health sciences, University of Macau, Taipa, Macao
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6078-1409

  6. Ruiwen Chen

    Faculty of health sciences, University of Macau, Taipa, Macao
    Competing interests
    The authors declare that no competing interests exist.

  7. Li Shen

    Faculty of health sciences, University of Macau, Taipa, Macao
    Competing interests
    The authors declare that no competing interests exist.

  8. Kaeling Tan

    Faculty of health sciences, University of Macau, Taipa, Macao
    Competing interests
    The authors declare that no competing interests exist.

  9. Koon Ho Wong

    Faculty of health sciences, University of Macau, Taipa, Macao
    For correspondence
    koonhowong@um.edu.mo
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9264-5118

Funding

Research Services and Knowledge Transfer Office, University of Macau (MYRG2019-00099-FHS)

  • Koon Ho Wong

Fundo para o Desenvolvimento das Ciências e da Tecnologia (0033/2021/A1)

  • Koon Ho Wong

Research Services and Knowledge Transfer Office, University of Macau (MYRG2022-00107-FHS)

  • Koon Ho Wong

Fundo para o Desenvolvimento das Ciências e da Tecnologia (0099/2022/A2)

  • Koon Ho Wong

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2024, Rai 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.

Metrics

  • 499
    views
  • 68
    downloads
  • 0
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Maruti Nandan Rai
  2. Qing Lan
  3. Chirag Parsania
  4. Rikky Rai
  5. Niranjan Shirgaonkar
  6. Ruiwen Chen
  7. Li Shen
  8. Kaeling Tan
  9. Koon Ho Wong
(2024)
Temporal transcriptional response of Candida glabrata during macrophage infection reveals a multifaceted transcriptional regulator CgXbp1 important for macrophage response and fluconazole resistance
eLife 13:e73832.
https://doi.org/10.7554/eLife.73832

Share this article

https://doi.org/10.7554/eLife.73832

Categories and tags

Further reading

    1. Biochemistry and Chemical Biology
    2. Chromosomes and Gene Expression

    Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome

    Kira A Cozzolino, Lynn Sanford ... Dylan J Taatjes
    Research Article

    Hyperactive interferon (IFN) signaling is a hallmark of Down syndrome (DS), a condition caused by Trisomy 21 (T21); strategies that normalize IFN signaling could benefit this population. Mediator-associated kinases CDK8 and CDK19 drive inflammatory responses through incompletely understood mechanisms. Using sibling-matched cell lines with/without T21, we investigated Mediator kinase function in the context of hyperactive IFN in DS over a 75 min to 24 hr timeframe. Activation of IFN-response genes was suppressed in cells treated with the CDK8/CDK19 inhibitor cortistatin A (CA), via rapid suppression of IFN-responsive transcription factor (TF) activity. We also discovered that CDK8/CDK19 affect splicing, a novel means by which Mediator kinases control gene expression. To further probe Mediator kinase function, we completed cytokine screens and metabolomics experiments. Cytokines are master regulators of inflammatory responses; by screening 105 different cytokine proteins, we show that Mediator kinases help drive IFN-dependent cytokine responses at least in part through transcriptional regulation of cytokine genes and receptors. Metabolomics revealed that Mediator kinase inhibition altered core metabolic pathways in cell type-specific ways, and broad upregulation of anti-inflammatory lipid mediators occurred specifically in kinase-inhibited cells during hyperactive IFNγ signaling. A subset of these lipids (e.g. oleamide, desmosterol) serve as ligands for nuclear receptors PPAR and LXR, and activation of these receptors occurred specifically during hyperactive IFN signaling in CA-treated cells, revealing mechanistic links between Mediator kinases, lipid metabolism, and nuclear receptor function. Collectively, our results establish CDK8/CDK19 as context-specific metabolic regulators, and reveal that these kinases control gene expression not only via TFs, but also through metabolic changes and splicing. Moreover, we establish that Mediator kinase inhibition antagonizes IFN signaling through transcriptional, metabolic, and cytokine responses, with implications for DS and other chronic inflammatory conditions.

    1. Chromosomes and Gene Expression

    Cryogenic Electron Microscopy: MagIC beads for scarce macromolecules

    Carlos Moreno-Yruela, Beat Fierz
    Insight

    Specialized magnetic beads that bind target proteins to a cryogenic electron microscopy grid make it possible to study the structure of protein complexes from dilute samples.

    1. Chromosomes and Gene Expression

    Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy

    Carmina Lichauco, Eric J Foss ... Antonio Bedalov
    Research Article

    The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA (rDNA) arrays. We have previously reported that in the absence of SIR2, a de-repressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the nondisplaced MCMs. Furthermore, we found that both activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler.