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NAD+ pool depletion as a signal for the Rex regulon involved in Streptococcus agalactiae virulence

Franza, Thierry ; Rogstam, Annika LU ; Thiyagarajan, Saravanamuthu ; Sullivan, Matthew J. ; Derré-Bobillot, Aurelie ; Bauer, Mikael C. LU ; Goh, Kelvin G.K. ; Cunha, Violette Da ; Glaser, Philippe and Logan, Derek T. LU orcid , et al. (2021) In PLoS Pathogens 17(8).
Abstract

In many Gram-positive bacteria, the redox-sensing transcriptional repressor Rex controls central carbon and energy metabolism by sensing the intra cellular balance between the reduced and oxidized forms of nicotinamide adenine dinucleotide; the NADH/NAD+ ratio. Here, we report high-resolution crystal structures and characterization of a Rex ortholog (Gbs1167) in the opportunistic pathogen, Streptococcus agalactiae, also known as group B streptococcus (GBS). We present structures of Rex bound to NAD+ and to a DNA operator which are the first structures of a Rex-family member from a pathogenic bacterium. The structures reveal the molecular basis of DNA binding and the conformation alterations between the free... (More)

In many Gram-positive bacteria, the redox-sensing transcriptional repressor Rex controls central carbon and energy metabolism by sensing the intra cellular balance between the reduced and oxidized forms of nicotinamide adenine dinucleotide; the NADH/NAD+ ratio. Here, we report high-resolution crystal structures and characterization of a Rex ortholog (Gbs1167) in the opportunistic pathogen, Streptococcus agalactiae, also known as group B streptococcus (GBS). We present structures of Rex bound to NAD+ and to a DNA operator which are the first structures of a Rex-family member from a pathogenic bacterium. The structures reveal the molecular basis of DNA binding and the conformation alterations between the free NAD+ complex and DNA-bound form of Rex. Transcriptomic analysis revealed that GBS Rex controls not only central metabolism, but also expression of the monocistronic rex gene as well as virulence gene expression. Rex enhances GBS virulence after disseminated infection in mice. Mechanistically, NAD+ stabilizes Rex as a repressor in the absence of NADH. However, GBS Rex is unique compared to Rex regulators previously characterized because of its sensing mechanism: we show that it primarily responds to NAD+ levels (or growth rate) rather than to the NADH/NAD+ ratio. These results indicate that Rex plays a key role in GBS pathogenicity by modulating virulence factor gene expression and carbon metabolism to harvest nutrients from the host.

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publishing date
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Contribution to journal
publication status
published
subject
in
PLoS Pathogens
volume
17
issue
8
article number
e1009791
publisher
Public Library of Science (PLoS)
external identifiers
  • pmid:34370789
  • scopus:85112610371
ISSN
1553-7366
DOI
10.1371/journal.ppat.1009791
language
English
LU publication?
yes
id
c623a35c-188f-43e1-b6c6-b05639b545c5
date added to LUP
2021-09-23 10:09:19
date last changed
2024-06-15 16:41:22
@article{c623a35c-188f-43e1-b6c6-b05639b545c5,
  abstract     = {{<p>In many Gram-positive bacteria, the redox-sensing transcriptional repressor Rex controls central carbon and energy metabolism by sensing the intra cellular balance between the reduced and oxidized forms of nicotinamide adenine dinucleotide; the NADH/NAD<sup>+</sup> ratio. Here, we report high-resolution crystal structures and characterization of a Rex ortholog (Gbs1167) in the opportunistic pathogen, Streptococcus agalactiae, also known as group B streptococcus (GBS). We present structures of Rex bound to NAD<sup>+</sup> and to a DNA operator which are the first structures of a Rex-family member from a pathogenic bacterium. The structures reveal the molecular basis of DNA binding and the conformation alterations between the free NAD<sup>+</sup> complex and DNA-bound form of Rex. Transcriptomic analysis revealed that GBS Rex controls not only central metabolism, but also expression of the monocistronic rex gene as well as virulence gene expression. Rex enhances GBS virulence after disseminated infection in mice. Mechanistically, NAD<sup>+</sup> stabilizes Rex as a repressor in the absence of NADH. However, GBS Rex is unique compared to Rex regulators previously characterized because of its sensing mechanism: we show that it primarily responds to NAD<sup>+</sup> levels (or growth rate) rather than to the NADH/NAD<sup>+</sup> ratio. These results indicate that Rex plays a key role in GBS pathogenicity by modulating virulence factor gene expression and carbon metabolism to harvest nutrients from the host.</p>}},
  author       = {{Franza, Thierry and Rogstam, Annika and Thiyagarajan, Saravanamuthu and Sullivan, Matthew J. and Derré-Bobillot, Aurelie and Bauer, Mikael C. and Goh, Kelvin G.K. and Cunha, Violette Da and Glaser, Philippe and Logan, Derek T. and Ulett, Glen C. and von Wachenfeldt, Claes and Gaudu, Philippe}},
  issn         = {{1553-7366}},
  language     = {{eng}},
  number       = {{8}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS Pathogens}},
  title        = {{NAD<sup>+</sup> pool depletion as a signal for the Rex regulon involved in Streptococcus agalactiae virulence}},
  url          = {{http://dx.doi.org/10.1371/journal.ppat.1009791}},
  doi          = {{10.1371/journal.ppat.1009791}},
  volume       = {{17}},
  year         = {{2021}},
}