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

Publication 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.

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  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

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