{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T07:42:30Z","timestamp":1773301350596,"version":"3.50.1"},"reference-count":33,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2016,4,19]],"date-time":"2016-04-19T00:00:00Z","timestamp":1461024000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2016,5,4]],"date-time":"2016-05-04T00:00:00Z","timestamp":1462320000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Veterans Administration","award":["IO1 BX002073"],"award-info":[{"award-number":["IO1 BX002073"]}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI54959"],"award-info":[{"award-number":["R01 AI54959"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["F32 AI108249"],"award-info":[{"award-number":["F32 AI108249"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["T32 GM008730"],"award-info":[{"award-number":["T32 GM008730"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["T32 AI052066"],"award-info":[{"award-number":["T32 AI052066"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["F31 AI118223"],"award-info":[{"award-number":["F31 AI118223"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2016,5,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The four-cysteine zinc finger motif of the bacterial RNA polymerase regulator DksA is essential for protein structure, canonical control of the stringent response to nutritional limitation, and thiol-based sensing of oxidative and nitrosative stress. This interdependent relationship has limited our understanding of DksA-mediated functions in bacterial pathogenesis. Here, we have addressed this challenge by complementing \u0394\n            <jats:italic>dksA Salmonella<\/jats:italic>\n            with\n            <jats:named-content content-type=\"genus-species\">Pseudomonas aeruginosa<\/jats:named-content>\n            <jats:italic>dksA<\/jats:italic>\n            paralogues that encode proteins differing in cysteine and zinc content. We find that four-cysteine, zinc-bound (C4) and two-cysteine, zinc-free (C2) DksA proteins are able to mediate appropriate stringent control in\n            <jats:italic>Salmonella<\/jats:italic>\n            and that thiol-based sensing of reactive species is conserved among C2 and C4 orthologues. However, variations in cysteine and zinc content determine the threshold at which individual DksA proteins sense and respond to reactive species. In particular, zinc acts as an antioxidant, dampening cysteine reactivity and raising the threshold of posttranslational thiol modification with reactive species. Consequently, C2 DksA triggers transcriptional responses in\n            <jats:italic>Salmonella<\/jats:italic>\n            at levels of oxidative or nitrosative stress normally tolerated by\n            <jats:italic>Salmonella<\/jats:italic>\n            expressing C4 orthologues. Inappropriate transcriptional regulation by C2 DksA increases the susceptibility of\n            <jats:italic>Salmonella<\/jats:italic>\n            to the antimicrobial effects of hydrogen peroxide and nitric oxide, and attenuates virulence in macrophages and mice. Our findings suggest that the redox-active sensory function of DksA proteins is finely tuned to optimize bacterial fitness according to the levels of oxidative and nitrosative stress encountered by bacterial species in their natural and host environments.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            In order to cause disease, pathogenic bacteria must rapidly sense and respond to antimicrobial pressures encountered within the host. Prominent among these stresses, and of particular relevance to intracellular pathogens such as\n            <jats:italic>Salmonella<\/jats:italic>\n            , are nutritional restriction and the enzymatic generation of reactive oxygen and nitrogen species. The conserved transcriptional regulator DksA controls adaptive responses to nutritional limitation, as well as to oxidative and nitrosative stress. Here, we demonstrate that each of these functions contributes to bacterial pathogenesis. Our observations highlight the importance of metabolic adaptation in bacterial pathogenesis and show the mechanism by which DksA orthologues are optimized to sense the levels of oxidative and nitrosative stress encountered in their natural habitats. An improved understanding of the conserved processes used by bacteria to sense, respond to, and limit host defense will inform the development of novel strategies to treat infections caused by pathogenic, potentially multidrug-resistant bacteria.\n          <\/jats:p>","DOI":"10.1128\/mbio.02161-15","type":"journal-article","created":{"date-parts":[[2016,4,20]],"date-time":"2016-04-20T01:13:21Z","timestamp":1461114801000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":41,"title":["Redox-Active Sensing by Bacterial DksA Transcription Factors Is Determined by Cysteine and Zinc Content"],"prefix":"10.1128","volume":"7","author":[{"given":"Matthew A.","family":"Crawford","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Tapscott","sequence":"additional","affiliation":[{"name":"Molecular Biology Program, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liam F.","family":"Fitzsimmons","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"An\u00edbal M.","family":"Reyes","sequence":"additional","affiliation":[{"name":"Departamento de Bioquimica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la Rep\u00fablica, Montevideo, Uruguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen J.","family":"Libby","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madia","family":"Trujillo","sequence":"additional","affiliation":[{"name":"Departamento de Bioquimica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la Rep\u00fablica, Montevideo, Uruguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ferric C.","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Radi","sequence":"additional","affiliation":[{"name":"Departamento de Bioquimica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la Rep\u00fablica, Montevideo, Uruguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9s","family":"V\u00e1zquez-Torres","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"},{"name":"Molecular Biology Program, University of Colorado School of Medicine, Aurora, Colorado, USA"},{"name":"Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado, 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