title: Antioxidant Defense by Thioredoxin Can Occur Independently of Canonical Thiol-Disulfide Oxidoreductase Enzymatic Activity.
abstract: The thiol-disulfide oxidoreductase CXXC catalytic domain of thioredoxin contributes to antioxidant defense in phylogenetically diverse organisms. We find that although the oxidoreductase activity of thioredoxin-1 protects Salmonella enterica serovar Typhimurium from hydrogen peroxide in vitro, it does not appear to contribute to Salmonella's antioxidant defenses in vivo. Nonetheless, thioredoxin-1 defends Salmonella from oxidative stress resulting from NADPH phagocyte oxidase macrophage expression during the innate immune response in mice. Thioredoxin-1 binds to the flexible linker, which connects the receiver and effector domains of SsrB, thereby keeping this response regulator in the soluble fraction. Thioredoxin-1, independently of thiol-disulfide exchange, activates intracellular SPI2 gene transcription required for Salmonella resistance to both reactive species generated by NADPH phagocyte oxidase and oxygen-independent lysosomal host defenses. These findings suggest that the horizontally acquired virulence determinant SsrB is regulated post-translationally by ancestrally present thioredoxin.
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, 12800 East 19(th) Avenue, Aurora, CO 80045, USA.
authors.forename: Miryoung
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, 12800 East 19(th) Avenue, Aurora, CO 80045, USA.
authors.forename: Ju-Sim
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, 12800 East 19(th) Avenue, Aurora, CO 80045, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, 12800 East 19(th) Avenue, Aurora, CO 80045, USA; Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama, Birmingham, 619 South 19(th) Street, Birmingham, AL 35249-6810, USA.
authors.forename: Maroof
authors.initials: M
authors.lastname: Husain
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, 12800 East 19(th) Avenue, Aurora, CO 80045, USA; Veterans Affairs Eastern Colorado Health Care System, 1055 Clermont Street, Denver, CO 80220, USA. Electronic address: andres.vazquez-torres@ucdenver.edu.
authors.forename: Andrés
authors.initials: A
authors.lastname: Vázquez-Torres
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D020134:Catalytic Domain; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007113:Immunity, Innate; D008099:Liver / Q000382:microbiology; D008264:Macrophages / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D023421:Models, Animal; D019255:NADPH Oxidases / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D011485:Protein Binding; D011490:Protein Disulfide Reductase (Glutathione) / Q000378:metabolism; D000067996:RAW 264.7 Cells; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012485:Salmonella typhi / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D013879:Thioredoxins / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D001426:Bacterial Proteins; D008565:Membrane Proteins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C440638:SPI-2 protein, Salmonella; C119761:SsrB protein, Salmonella typhimurium; D014157:Transcription Factors; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D011490:Protein Disulfide Reductase (Glutathione)