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

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 crysta...

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Autores principales:	Thierry Franza, Annika Rogstam, Saravanamuthu Thiyagarajan, Matthew J Sullivan, Aurelie Derré-Bobillot, Mikael C Bauer, Kelvin G K Goh, Violette Da Cunha, Philippe Glaser, Derek T Logan, Glen C Ulett, Claes von Wachenfeldt, Philippe Gaudu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3ee0357565124674bb62d93dadb56787
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spelling	oai:doaj.org-article:3ee0357565124674bb62d93dadb567872021-12-02T20:00:24ZNAD+ pool depletion as a signal for the Rex regulon involved in Streptococcus agalactiae virulence.1553-73661553-737410.1371/journal.ppat.1009791https://doaj.org/article/3ee0357565124674bb62d93dadb567872021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009791https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374In 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.Thierry FranzaAnnika RogstamSaravanamuthu ThiyagarajanMatthew J SullivanAurelie Derré-BobillotMikael C BauerKelvin G K GohViolette Da CunhaPhilippe GlaserDerek T LoganGlen C UlettClaes von WachenfeldtPhilippe GauduPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 8, p e1009791 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Thierry Franza Annika Rogstam Saravanamuthu Thiyagarajan Matthew J Sullivan Aurelie Derré-Bobillot Mikael C Bauer Kelvin G K Goh Violette Da Cunha Philippe Glaser Derek T Logan Glen C Ulett Claes von Wachenfeldt Philippe Gaudu NAD+ pool depletion as a signal for the Rex regulon involved in Streptococcus agalactiae virulence.
description	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.
format	article
author	Thierry Franza Annika Rogstam Saravanamuthu Thiyagarajan Matthew J Sullivan Aurelie Derré-Bobillot Mikael C Bauer Kelvin G K Goh Violette Da Cunha Philippe Glaser Derek T Logan Glen C Ulett Claes von Wachenfeldt Philippe Gaudu
author_facet	Thierry Franza Annika Rogstam Saravanamuthu Thiyagarajan Matthew J Sullivan Aurelie Derré-Bobillot Mikael C Bauer Kelvin G K Goh Violette Da Cunha Philippe Glaser Derek T Logan Glen C Ulett Claes von Wachenfeldt Philippe Gaudu
author_sort	Thierry Franza
title	NAD+ pool depletion as a signal for the Rex regulon involved in Streptococcus agalactiae virulence.
title_short	NAD+ pool depletion as a signal for the Rex regulon involved in Streptococcus agalactiae virulence.
title_full	NAD+ pool depletion as a signal for the Rex regulon involved in Streptococcus agalactiae virulence.
title_fullStr	NAD+ pool depletion as a signal for the Rex regulon involved in Streptococcus agalactiae virulence.
title_full_unstemmed	NAD+ pool depletion as a signal for the Rex regulon involved in Streptococcus agalactiae virulence.
title_sort	nad+ pool depletion as a signal for the rex regulon involved in streptococcus agalactiae virulence.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/3ee0357565124674bb62d93dadb56787
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NAD+ pool depletion as a signal for the Rex regulon involved in Streptococcus agalactiae virulence.

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