A single regulator NrtR controls bacterial NAD+ homeostasis via its acetylation
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.
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
National Natural Science Foundation of China (31830001)
- Youjun Feng
National Key R&D Program of China (2017YFD0500202)
- Youjun Feng
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Bavesh D Kana, University of the Witwatersrand, South Africa
- Received: September 4, 2019
- Accepted: October 4, 2019
- Accepted Manuscript published: October 9, 2019 (version 1)
- Accepted Manuscript updated: October 10, 2019 (version 2)
- Accepted Manuscript updated: October 10, 2019 (version 3)
- Version of Record published: October 18, 2019 (version 4)
© 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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