A single regulator NrtR controls bacterial NAD+ homeostasis via its acetylation
- Zhejiang University School of Medicine, China
- Stony Brook University, United States
- Zhejiang University of Technology, China
- 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.
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Author details
Funding
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.
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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A single regulator NrtR controls bacterial NAD+ homeostasis via its acetylation
eLife 8:e51603.
https://doi.org/10.7554/eLife.51603
Further reading
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- Microbiology and Infectious Disease
Pathogenic and nonpathogenic mycobacteria secrete extracellular vesicles (EVs) under various conditions. EVs produced by Mycobacterium tuberculosis (Mtb) have raised significant interest for their potential in cell communication, nutrient acquisition, and immune evasion. However, the relevance of vesicle secretion during tuberculosis infection remains unknown due to the limited understanding of mycobacterial vesicle biogenesis. We have previously shown that a transposon mutant in the LCP-related gene virR (virRmut) manifested a strong attenuated phenotype during experimental macrophage and murine infections, concomitant to enhanced vesicle release. In this study, we aimed to understand the role of VirR in the vesicle production process in Mtb. We employ genetic, transcriptional, proteomics, ultrastructural, and biochemical methods to investigate the underlying processes explaining the enhanced vesiculogenesis phenomenon observed in the virRmut. Our results establish that VirR is critical to sustain proper cell permeability via regulation of cell envelope remodeling possibly through the interaction with similar cell envelope proteins, which control the link between peptidoglycan and arabinogalactan. These findings advance our understanding of mycobacterial extracellular vesicle biogenesis and suggest that these set of proteins could be attractive targets for therapeutic intervention.
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- Epidemiology and Global Health
- Microbiology and Infectious Disease
Background:
In many settings, a large fraction of the population has both been vaccinated against and infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hence, quantifying the protection provided by post-infection vaccination has become critical for policy. We aimed to estimate the protective effect against SARS-CoV-2 reinfection of an additional vaccine dose after an initial Omicron variant infection.
Methods:
We report a retrospective, population-based cohort study performed in Shanghai, China, using electronic databases with information on SARS-CoV-2 infections and vaccination history. We compared reinfection incidence by post-infection vaccination status in individuals initially infected during the April–May 2022 Omicron variant surge in Shanghai and who had been vaccinated before that period. Cox models were fit to estimate adjusted hazard ratios (aHRs).
Results:
275,896 individuals were diagnosed with real-time polymerase chain reaction-confirmed SARS-CoV-2 infection in April–May 2022; 199,312/275,896 were included in analyses on the effect of a post-infection vaccine dose. Post-infection vaccination provided protection against reinfection (aHR 0.82; 95% confidence interval 0.79–0.85). For patients who had received one, two, or three vaccine doses before their first infection, hazard ratios for the post-infection vaccination effect were 0.84 (0.76–0.93), 0.87 (0.83–0.90), and 0.96 (0.74–1.23), respectively. Post-infection vaccination within 30 and 90 days before the second Omicron wave provided different degrees of protection (in aHR): 0.51 (0.44–0.58) and 0.67 (0.61–0.74), respectively. Moreover, for all vaccine types, but to different extents, a post-infection dose given to individuals who were fully vaccinated before first infection was protective.
Conclusions:
In previously vaccinated and infected individuals, an additional vaccine dose provided protection against Omicron variant reinfection. These observations will inform future policy decisions on COVID-19 vaccination in China and other countries.
Funding:
This study was funded the Key Discipline Program of Pudong New Area Health System (PWZxk2022-25), the Development and Application of Intelligent Epidemic Surveillance and AI Analysis System (21002411400), the Shanghai Public Health System Construction (GWVI-11.2-XD08), the Shanghai Health Commission Key Disciplines (GWVI-11.1-02), the Shanghai Health Commission Clinical Research Program (20214Y0020), the Shanghai Natural Science Foundation (22ZR1414600), and the Shanghai Young Health Talents Program (2022YQ076).
