{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:39:24Z","timestamp":1792651164201,"version":"4.5.0"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T00:00:00Z","timestamp":1629244800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1P01 AI063302"],"award-info":[{"award-number":["1P01 AI063302"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01 AI27655"],"award-info":[{"award-number":["1R01 AI27655"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"national science foundation","doi-asserted-by":"publisher","award":["DGE 1752814"],"award-info":[{"award-number":["DGE 1752814"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p><jats:italic>Listeria monocytogenes<\/jats:italic> is a Gram-positive, food-borne pathogen that lives a biphasic lifestyle, cycling between the environment and as a facultative intracellular pathogen of mammals. Upon entry into host cells, <jats:italic>L<\/jats:italic>. <jats:italic>monocytogenes<\/jats:italic> upregulates expression of glutathione synthase (GshF) and its product, glutathione (GSH), which is an allosteric activator of the master virulence regulator PrfA. Although <jats:italic>gshF<\/jats:italic> mutants are highly attenuated for virulence in mice and form very small plaques in host cell monolayers, these virulence defects can be fully rescued by mutations that lock PrfA in its active conformation, referred to as PrfA*. While PrfA activation can be recapitulated <jats:italic>in vitro<\/jats:italic> by the addition of reducing agents, the precise biological cue(s) experienced by <jats:italic>L<\/jats:italic>. <jats:italic>monocytogenes<\/jats:italic> that lead to PrfA activation are not known. Here we performed a genetic screen to identify additional small-plaque mutants that were rescued by PrfA* and identified <jats:italic>gloA<\/jats:italic>, which encodes glyoxalase A, a component of a GSH-dependent methylglyoxal (MG) detoxification system. MG is a toxic byproduct of metabolism produced by both the host and pathogen, which if accumulated, causes DNA damage and protein glycation. As a facultative intracellular pathogen, <jats:italic>L<\/jats:italic>. <jats:italic>monocytogenes<\/jats:italic> must protect itself from MG produced by its own metabolic processes and that of its host. We report that <jats:italic>gloA<\/jats:italic> mutants grow normally in broth, are sensitive to exogenous MG and severely attenuated upon IV infection in mice, but are fully rescued for virulence in a PrfA* background. We demonstrate that transcriptional activation of <jats:italic>gshF<\/jats:italic> increased upon MG challenge <jats:italic>in vitro<\/jats:italic>, and while this resulted in higher levels of GSH for wild-type <jats:italic>L<\/jats:italic>. <jats:italic>monocytogenes<\/jats:italic>, the glyoxalase mutants had decreased levels of GSH, presumably due to the accumulation of the GSH-MG hemithioacetal adduct. These data suggest that MG acts as a host cue that leads to GSH production and activation of PrfA.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009819","type":"journal-article","created":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T17:36:32Z","timestamp":1629308192000},"page":"e1009819","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":61,"title":["Detoxification of methylglyoxal by the glyoxalase system is required for glutathione availability and virulence activation in Listeria monocytogenes"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2704-5562","authenticated-orcid":true,"given":"Andrea","family":"Anaya-Sanchez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Berude","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1218-2799","authenticated-orcid":true,"given":"Daniel A.","family":"Portnoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,8,18]]},"reference":[{"issue":"1","key":"ppat.1009819.ref001","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/nrmicro.2017.126","article-title":"Listeria monocytogenes: towards a complete picture of its physiology and pathogenesis","volume":"16","author":"L Radoshevich","year":"2018","journal-title":"Nat Rev Microbiol"},{"issue":"9","key":"ppat.1009819.ref002","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nrmicro2171","article-title":"Listeria monocytogenes\u2014from saprophyte to intracellular pathogen","volume":"7","author":"NE Freitag","year":"2009","journal-title":"Nat Rev 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