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Formaldehyde is a universal stressor and potent metabolic toxin that is generated in organisms from bacteria to humans. Methylotrophic bacteria such as\n                    <jats:italic>Methylorubrum extorquens<\/jats:italic>\n                    face an acute challenge due to their production of formaldehyde as an obligate central intermediate of single-carbon metabolism. Mechanisms to sense and respond to formaldehyde were speculated to exist in methylotrophs for decades but had never been discovered. Here, we identify a member of the DUF336 domain family, named\n                    <jats:italic>efgA<\/jats:italic>\n                    for enhanced formaldehyde growth, that plays an important role in endogenous formaldehyde stress response in\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>extorquens<\/jats:italic>\n                    PA1 and is found almost exclusively in methylotrophic taxa. Our experimental analyses reveal that EfgA is a formaldehyde sensor that rapidly arrests growth in response to elevated levels of formaldehyde. Heterologous expression of EfgA in\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    increases formaldehyde resistance, indicating that its interaction partners are widespread and conserved. EfgA represents the first example of a formaldehyde stress response system that does not involve enzymatic detoxification. Thus, EfgA comprises a unique stress response mechanism in bacteria, whereby a single protein directly senses elevated levels of a toxic intracellular metabolite and safeguards cells from potential damage.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3001208","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T13:24:58Z","timestamp":1622035498000},"page":"e3001208","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":33,"title":["EfgA is a conserved formaldehyde sensor that leads to bacterial growth arrest in response to elevated formaldehyde"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9012-2260","authenticated-orcid":true,"given":"Jannell V.","family":"Bazurto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipti D.","family":"Nayak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomislav","family":"Ticak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milya","family":"Davlieva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0250-4064","authenticated-orcid":true,"given":"Jessica A.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7694-0715","authenticated-orcid":true,"given":"Chandler N.","family":"Hellenbrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah B.","family":"Lambert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia J.","family":"Benski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6750-1876","authenticated-orcid":true,"given":"Caleb J.","family":"Quates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3881-722X","authenticated-orcid":true,"given":"Jill L.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4999-5347","authenticated-orcid":true,"given":"Jagdish Suresh","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7439-8224","authenticated-orcid":true,"given":"F. 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