1. Role of the global regulator Rex in control of NAD + ‐regeneration in Clostridioides (Clostridium) difficile
- Author
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Thomas Dubois, Marc Monot, Michael B. Francis, Laurent Bouillaut, Abraham L. Sonenshein, Bruno Dupuy, Nadine Daou, Joseph A. Sorg, Tufts University School of Medicine [Boston], Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7), Texas A&M University [College Station], Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris], This work was supported by research grants from the US National Institute of General Medical Sciences (R01GM042219) to ALS and from the US National Institute of Allergy and Infectious Diseases (R56AI108987) to JAS, and was funded by the Institut Pasteur and by Integrative Biology of Emerging Infectious Diseases (LabEX IBEID) as part of the framework of the French Government’s ‘Programme Investissements d’Avenir’. This work was also supported by an American Heart Association National Scientist Development grant to JAS (No. 11SDG7160013) and by a Roux Fellowship (Institut Pasteur) to TD., We thank Boris Belitsky for helpful suggestions and discussions during the course of this work and Audrey Hamiot for verifying the location of the rex mutation and providing the growth curves of the various strains., ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7), and Institut Pasteur [Paris] (IP)
- Subjects
proline reductase ,Proline ,[SDV]Life Sciences [q-bio] ,Reductase ,Biology ,Microbiology ,Glycine reductase ,Article ,toxin production ,03 medical and health sciences ,Clostridium ,enzymic reduction ,Multienzyme Complexes ,expression ,Animals ,Regeneration ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Molecular Biology ,bacillus-subtilis ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,amino acids ,repressor ,Mesocricetus ,Clostridioides difficile ,030306 microbiology ,Stickland reaction ,Gene Expression Regulation, Bacterial ,NAD ,biology.organism_classification ,Amino acid ,Gene Products, rex ,virulence ,anaerobes genus clostridium ,Biochemistry ,chemistry ,comic_books ,Female ,Fermentation ,Amino Acid Oxidoreductases ,NAD+ kinase ,Isoleucine ,Oxidation-Reduction ,metabolism ,comic_books.character - Abstract
International audience; For the human pathogen Clostridioides (also known as Clostridium) difficile, the ability to adapt to nutrient availability is critical for its proliferation and production of toxins during infection. Synthesis of the toxins is regulated by the availability of certain carbon sources, fermentation products and amino acids (e.g. proline, cysteine, isoleucine, leucine and valine). The effect of proline is attributable at least in part to its role as an inducer and substrate of D-proline reductase (PR), a Stickland reaction that regenerates NAD+ from NADH. Many Clostridium spp. use Stickland metabolism (co-fermentation of pairs of amino acids) to generate ATP and NAD+ . Synthesis of PR is activated by PrdR, a proline-responsive regulatory protein. Here we report that PrdR, in the presence of proline, represses other NAD+ -generating pathways, such as the glycine reductase and succinate-acetyl CoA utilization pathways leading to butyrate production, but does so indirectly by affecting the activity of Rex, a global redox-sensing regulator that responds to the NAD+ /NADH ratio. Our results indicate that PR activity is the favored mechanism for NAD+ regeneration and that both Rex and PrdR influence toxin production. Using the hamster model of C. difficile infection, we revealed the importance of PrdR-regulated Stickland metabolism in the virulence of C. difficile.
- Published
- 2019
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