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In bacteria, iron homeostasis involves Fur-mediated de-repression of iron uptake systems, such as the iron-chelating compounds siderophores. In this work, we identified and characterized novel regulatory systems that control siderophores in the environmental opportunistic pathogen\n              <jats:italic>Chromobacterium violaceum<\/jats:italic>\n              . Screening of a 10,000-transposon mutant library for siderophore halos identified seven possible regulatory systems involved in siderophore-mediated iron homeostasis in\n              <jats:italic>C. violaceum<\/jats:italic>\n              . Further characterization revealed a regulatory cascade that controls siderophores involving the transcription factor VitR acting upstream of the quorum-sensing (QS) system CviIR. Mutation of the regulator VitR led to an increase in siderophore halos, and a decrease in biofilm, violacein, and protease production. We determined that these effects occurred due to VitR-dependent de-repression of\n              <jats:italic>vioS<\/jats:italic>\n              . Increased VioS leads to direct inhibition of the CviR regulator by protein-protein interaction. Indeed, insertion mutations in\n              <jats:italic>cviR<\/jats:italic>\n              and null mutations of\n              <jats:italic>cviI<\/jats:italic>\n              and\n              <jats:italic>cviR<\/jats:italic>\n              led to an increase of siderophore halos. RNA-seq of the\n              <jats:italic>cviI<\/jats:italic>\n              and\n              <jats:italic>cviR<\/jats:italic>\n              mutants revealed that CviR regulates CviI-dependent and CviI-independent regulons. Classical QS-dependent processes (violacein, proteases, and antibiotics) were activated at high cell density by both CviI and CviR. However, genes related to iron homeostasis and many other processes were regulated by CviR but not CviI, suggesting that CviR acts without its canonical CviI autoinducer. Our data revealed a complex regulatory cascade involving QS that controls siderophore-mediated iron homeostasis in\n              <jats:italic>C. violaceum<\/jats:italic>\n              .\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                The iron-chelating compounds siderophores play a major role in bacterial iron acquisition. Here, we employed a genetic screen to identify novel siderophore regulatory systems in\n                <jats:italic>Chromobacterium violaceum<\/jats:italic>\n                , an opportunistic human pathogen. Many mutants with increased siderophore halos had transposon insertions in genes encoding transcription factors, including a novel regulator called VitR, and CviR, the regulator of the quorum-sensing (QS) system CviIR. We found that VitR is upstream in the pathway and acts as a dedicated repressor of\n                <jats:italic>vioS<\/jats:italic>\n                , which encodes a direct CviR-inhibitory protein. Indeed, all QS-related phenotypes of a\n                <jats:italic>vitR<\/jats:italic>\n                mutant were rescued in a\n                <jats:italic>vitRvioS<\/jats:italic>\n                mutant. At high cell density, CviIR activated classical QS-dependent processes (violacein, proteases, and antibiotics production). However, genes related to iron homeostasis and type-III and type-VI secretion systems were regulated by CviR in a CviI- or cell density-independent manner. Our data unveil a complex regulatory cascade integrating QS and siderophores in\n                <jats:italic>C. violaceum<\/jats:italic>\n                .\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/msystems.01397-23","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T13:05:27Z","timestamp":1710853527000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["A quorum-sensing regulatory cascade for siderophore-mediated iron homeostasis in\n            <i>Chromobacterium violaceum<\/i>"],"prefix":"10.1128","volume":"9","author":[{"given":"Bianca B.","family":"Batista","sequence":"first","affiliation":[{"name":"Departamento de Biologia Celular e Molecular e Bioagentes Patog\u00eanicos, Faculdade de Medicina de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinicius M.","family":"de Lima","sequence":"additional","affiliation":[{"name":"Departamento de Biologia Celular e Molecular e Bioagentes Patog\u00eanicos, Faculdade de Medicina de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz A.","family":"Picinato","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica e Imunologia, Faculdade de Medicina de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tie","family":"Koide","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica e Imunologia, Faculdade de Medicina de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto, S\u00e3o Paulo, 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