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It produces four different types of terminal oxidases for aerobic respiration, and for one of these, the\n            <jats:italic>cbb<\/jats:italic>\n            <jats:sub>3<\/jats:sub>\n            -type terminal oxidases, it has the capacity to produce at least 16 isoforms encoded by partially redundant operons. It also produces small-molecule virulence factors that interact with the respiratory chain, including the poison cyanide. Previous studies had indicated a role for cyanide in activating expression of an \u201corphan\u201d terminal oxidase subunit gene called\n            <jats:italic>ccoN4<\/jats:italic>\n            and that the product contributes to\n            <jats:italic>P. aeruginosa<\/jats:italic>\n            cyanide resistance, fitness in biofilms, and virulence, but the mechanisms underlying this process had not been elucidated. Here, we show that the regulatory protein MpaR, which is predicted to be a pyridoxal phosphate-binding transcription factor and is encoded just upstream of\n            <jats:italic>ccoN4<\/jats:italic>\n            , controls\n            <jats:italic>ccoN4<\/jats:italic>\n            expression in response to endogenous cyanide. Paradoxically, we find that cyanide production is required to support CcoN4\u2019s contribution to respiration in biofilms. We identify a palindromic motif required for cyanide- and MpaR-dependent expression of\n            <jats:italic>ccoN4<\/jats:italic>\n            and co-expressed adjacent loci. We also characterize the regulatory logic of this region of the chromosome. Finally, we identify residues in the putative cofactor-binding pocket of MpaR, which are required for\n            <jats:italic>ccoN4<\/jats:italic>\n            expression. Together, our findings illustrate a novel scenario in which the respiratory toxin cyanide acts as a signal to control gene expression in a bacterium that produces the compound endogenously.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Cyanide is an inhibitor of heme-copper oxidases, which are required for aerobic respiration in all eukaryotes and many prokaryotes. This fast-acting poison can arise from diverse sources, but mechanisms by which bacteria sense it are poorly understood. We investigated the regulatory response to cyanide in the pathogenic bacterium\n              <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n              , which produces cyanide as a virulence factor. Although\n              <jats:italic>P. aeruginosa<\/jats:italic>\n              has the capacity to produce a cyanide-resistant oxidase, it relies primarily on heme-copper oxidases and even makes additional heme-copper oxidase proteins specifically under cyanide-producing conditions. We found that the protein MpaR controls expression of cyanide-inducible genes in\n              <jats:italic>P. aeruginosa<\/jats:italic>\n              and elucidated the molecular details of this regulation. MpaR contains a DNA-binding domain and a domain predicted to bind pyridoxal phosphate (vitamin B6), a compound that is known to react spontaneously with cyanide. These observations provide insight into the understudied phenomenon of cyanide-dependent regulation of gene expression in bacteria.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.02926-23","type":"journal-article","created":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T14:04:39Z","timestamp":1702994679000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["MpaR-driven expression of an orphan terminal oxidase subunit supports\n            <i>Pseudomonas aeruginosa<\/i>\n            biofilm respiration and development during cyanogenesis"],"prefix":"10.1128","volume":"15","author":[{"given":"Marina K.","family":"Smiley","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Columbia University, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doran C.","family":"Sekaran","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Columbia University, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farhad","family":"Forouhar","sequence":"additional","affiliation":[{"name":"Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Wolin","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Columbia University, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marko","family":"Jovanovic","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Columbia University, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa","family":"Price-Whelan","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Columbia University, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2049-1137","authenticated-orcid":true,"given":"Lars E. 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