Clp protease and antisense RNA jointly regulate the global regulator CarD to mediate mycobacterial starvation response

  1. Xinfeng Li
  2. Fang Chen
  3. Xiaoyu Liu
  4. Jinfeng Xiao
  5. Binda T Andongma
  6. Qing Tang
  7. Xiaojian Cao
  8. Shan-Ho Chou
  9. Michael Y Galperin
  10. Jin He  Is a corresponding author
  1. Huazhong Agricultural University, China
  2. National Institutes of Health, United States

Abstract

Under starvation conditions, bacteria tend to slow down their translation rate by reducing rRNA synthesis, but the way they accomplish that may vary in different bacteria. In Mycobacterium species, transcription of rRNA is activated by the RNA polymerase (RNAP) accessory transcription factor CarD, which interacts directly with RNAP to stabilize the RNAP-promoter open complex formed on rRNA genes. The functions of CarD have been extensively studied, but the mechanisms that control its expression remain obscure. Here, we report that the level of CarD was tightly regulated when mycobacterial cells switched from nutrient-rich to nutrient-deprived conditions. At the translational level, an antisense RNA of carD (AscarD) was induced in a SigF-dependent manner to bind with carD mRNA and inhibit CarD translation, while at the post-translational level, the residual intracellular CarD was quickly degraded by the Clp protease. AscarD thus worked synergistically with Clp protease to decrease the CarD level to help mycobacterial cells cope with the nutritional stress. Altogether, our work elucidates the regulation mode of CarD and delineates a new mechanism for the mycobacterial starvation response, which is important for the adaptation and persistence of mycobacterial pathogens in the host environment.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1, 4, 5 and 6. These Source Data contain the numerical data used to generate the figures.

Article and author information

Author details

  1. Xinfeng Li

    College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Fang Chen

    College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1663-3737
  3. Xiaoyu Liu

    College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Jinfeng Xiao

    College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Binda T Andongma

    College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Qing Tang

    College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Xiaojian Cao

    College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Shan-Ho Chou

    College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Michael Y Galperin

    National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2265-5572
  10. Jin He

    College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
    For correspondence
    hejin@mail.hzau.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1456-8284

Funding

National Natural Science Foundation of China (31770087)

  • Jin He

National Natural Science Foundation of China (31900057)

  • Qing Tang

National Natural Science Foundation of China (31970074)

  • Jin He

National Natural Science Foundation of China (32171424)

  • Jin He

China Postdoctoral Science Foundation (2019M662654)

  • Xinfeng Li

Intramural Research Program of the U.S. National Library of Medicine at the NIH

  • Michael Y Galperin

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

Reviewing Editor

  1. Bavesh D Kana, University of the Witwatersrand, South Africa

Version history

  1. Preprint posted: April 15, 2021 (view preprint)
  2. Received: August 25, 2021
  3. Accepted: January 25, 2022
  4. Accepted Manuscript published: January 26, 2022 (version 1)
  5. Version of Record published: February 7, 2022 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 1,575
    Page views
  • 253
    Downloads
  • 4
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Xinfeng Li
  2. Fang Chen
  3. Xiaoyu Liu
  4. Jinfeng Xiao
  5. Binda T Andongma
  6. Qing Tang
  7. Xiaojian Cao
  8. Shan-Ho Chou
  9. Michael Y Galperin
  10. Jin He
(2022)
Clp protease and antisense RNA jointly regulate the global regulator CarD to mediate mycobacterial starvation response
eLife 11:e73347.
https://doi.org/10.7554/eLife.73347

Share this article

https://doi.org/10.7554/eLife.73347

Further reading

    1. Microbiology and Infectious Disease
    Serge Pelet
    Insight

    Experiments involving periodic stimuli shed light on the interplay between hyper-osmotic stress and glucose starvation in yeast cells.

    1. Microbiology and Infectious Disease
    Bo Lyu, Qisheng Song
    Short Report

    The dynamic interplay between guanine-quadruplex (G4) structures and pathogenicity islands (PAIs) represents a captivating area of research with implications for understanding the molecular mechanisms underlying pathogenicity. This study conducted a comprehensive analysis of a large-scale dataset from reported 89 pathogenic strains of bacteria to investigate the potential interactions between G4 structures and PAIs. G4 structures exhibited an uneven and non-random distribution within the PAIs and were consistently conserved within the same pathogenic strains. Additionally, this investigation identified positive correlations between the number and frequency of G4 structures and the GC content across different genomic features, including the genome, promoters, genes, tRNA, and rRNA regions, indicating a potential relationship between G4 structures and the GC-associated regions of the genome. The observed differences in GC content between PAIs and the core genome further highlight the unique nature of PAIs and underlying factors, such as DNA topology. High-confidence G4 structures within regulatory regions of Escherichia coli were identified, modulating the efficiency or specificity of DNA integration events within PAIs. Collectively, these findings pave the way for future research to unravel the intricate molecular mechanisms and functional implications of G4-PAI interactions, thereby advancing our understanding of bacterial pathogenicity and the role of G4 structures in pathogenic diseases.