A single regulator NrtR controls bacterial NAD+ homeostasis via its acetylation

  1. Rongsui Gao
  2. Wenhui Wei
  3. Bachar H Hassan
  4. Jun Li
  5. Jiaoyu Deng
  6. Youjun Feng  Is a corresponding author
  1. Zhejiang University School of Medicine, China
  2. Stony Brook University, United States
  3. Zhejiang University of Technology, China
  4. Chinese Academy of Sciences, China

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an indispensable cofactor in all domains of life, the homeostasis of which requires tight regulation. Here we report that a Nudix-related transcriptional factor, designated MsNrtR (MSMEG_3198), controls the de novo pathway of NAD+ biosynthesis in M. smegmatis, a non-tuberculosis Mycobacterium. The integrated evidence in vitro and in vivo confirms that MsNrtR is an auto-repressor, and negatively controls the de novo NAD+ biosynthetic pathway. Binding of MsNrtR cognate DNA is finely mapped, which can be disrupted by an ADP-ribose intermediate. Unexpectedly, we discover that the acetylation of MsNrtR at Lysine 134 participates in the homeostasis of intra-cellular NAD+ level in M. smegmatis. Furthermore, we demonstrate that NrtR acetylation proceeds via the non-enzymatic acetyl-phosphate (AcP) route rather than the enzymatic Pat/CobB pathway. In addition, the acetylation of NrtR also occurs in its paralogs of Gram-positive bacterium Streptococcus and Gram-negative bacterium Vibrio, suggesting a common mechanism of post-translational modification in the context of NAD+ homeostasis. Together, it represents a first paradigm for the recruitment of acetylated NrtR to regulate bacterial central NAD+ metabolism.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Rongsui Gao

    Department of Pathogen Biology and Microbiology and Department of General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Wenhui Wei

    Department of Pathogen Biology and Microbiology and Department of General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Bachar H Hassan

    Stony Brook University, Stony Brook, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jun Li

    College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Jiaoyu Deng

    Key Laboratory of Agricultural and Environmental Microbiology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Youjun Feng

    Department of Pathogen Biology and Microbiology and Department of General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    For correspondence
    fengyj@zju.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8083-0175

Funding

National Natural Science Foundation of China (31830001)

  • Youjun Feng

National Key R&D Program of China (2017YFD0500202)

  • Youjun Feng

National Natural Science Foundation of China (81772142)

  • Youjun Feng

National Natural Science Foundation of China (31570027)

  • Youjun Feng

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. Received: September 4, 2019
  2. Accepted: October 4, 2019
  3. Accepted Manuscript published: October 9, 2019 (version 1)
  4. Accepted Manuscript updated: October 10, 2019 (version 2)
  5. Accepted Manuscript updated: October 10, 2019 (version 3)
  6. Version of Record published: October 18, 2019 (version 4)

Copyright

© 2019, Gao 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. Rongsui Gao
  2. Wenhui Wei
  3. Bachar H Hassan
  4. Jun Li
  5. Jiaoyu Deng
  6. Youjun Feng
(2019)
A single regulator NrtR controls bacterial NAD+ homeostasis via its acetylation
eLife 8:e51603.
https://doi.org/10.7554/eLife.51603

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