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NAD+ pool depletion as a signal for the Rex regulon involved in Streptococcus agalactiae virulence
- Source :
- PLoS Pathogens, PLoS Pathogens, Public Library of Science, 2021, 17 (8), pp.e1009791. ⟨10.1371/journal.ppat.1009791⟩, PLoS Pathogens, 2021, 17 (8), pp.e1009791. ⟨10.1371/journal.ppat.1009791⟩, PLoS Pathogens, Vol 17, Iss 8, p e1009791 (2021)
- Publication Year :
- 2021
-
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 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.<br />Author summary The Rex family transcription repressors serve critical roles in control of cellular metabolism. Pathogenic microorganisms often use metabolic cues to regulate their metabolism and virulence functions. Here, we structurally and functionally characterized Rex in the facultative aerobic Gram-positive coccus Streptococcus agalactiae, also known as group B streptococcus (GBS). GBS is a leading cause of meningitis in newborn babies and infants. Rex interacts with both the oxidized and reduced form of the cofactor nicotinamide adenine dinucleotide (NAD). The reduced form (NADH) abrogates DNA binding whereas the oxidized form (NAD+) enhance binding of Rex to DNA. We show that the cellular concentration of NAD+ is the main effector of Rex binding to DNA. A drop in the concentration of NAD+ is triggered when cells do not find a specific sugar such as glucose in the environment. Transcriptomic analysis revealed that GBS Rex controls not only central metabolism, but also its own expression as well as virulence gene expression. Together our results identify GBS Rex as an important transcription regulator critical for GBS pathogenicity by modulating virulence factor gene expression and carbon metabolism to efficiently utilize nutrient resources provided by the host.
- Subjects :
- Protein Conformation
viruses
[SDV]Life Sciences [q-bio]
Gene Expression
Electrophoretic Mobility Shift Assay
Restriction Fragment Mapping
Crystallography, X-Ray
Biochemistry
Mice
Biology (General)
Materials
Mice, Inbred BALB C
Organic Compounds
Nucleotides
Monosaccharides
Gene Pool
Gene Products, rex
Chemistry
Physical Sciences
Female
Protein Binding
Research Article
QH301-705.5
Materials Science
Carbohydrates
Research and Analysis Methods
Regulon
Streptococcus agalactiae
Bacterial Proteins
Streptococcal Infections
Genetics
Animals
Gene Regulation
Molecular Biology Techniques
Dimers
Molecular Biology
Regulons
Evolutionary Biology
Population Biology
Gene Expression Profiling
Organic Chemistry
Gene Mapping
Chemical Compounds
Biology and Life Sciences
Galactose
RC581-607
biochemical phenomena, metabolism, and nutrition
NAD
Polymer Chemistry
Mice, Inbred C57BL
virulence
Glucose
Oligomers
Immunologic diseases. Allergy
Population Genetics
Subjects
Details
- Language :
- English
- ISSN :
- 15537366 and 15537374
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens, PLoS Pathogens, Public Library of Science, 2021, 17 (8), pp.e1009791. ⟨10.1371/journal.ppat.1009791⟩, PLoS Pathogens, 2021, 17 (8), pp.e1009791. ⟨10.1371/journal.ppat.1009791⟩, PLoS Pathogens, Vol 17, Iss 8, p e1009791 (2021)
- Accession number :
- edsair.pmid.dedup....15dec3840537481b9ba4d9fbb9c1ad7d