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Antibiotic therapy has been the conventional treatment for such infections, but its efficacy has decreased due to the emergence of antibiotic-resistant bacteria. Identification and characterization of bacterial factors that contribute to the severity of infection would facilitate the development of novel therapeutic strategies. The ExPEC periplasmic protease Prc contributes to the pathogen\u2019s ability to evade complement-mediated killing in the serum. Here, we further investigated the role of the Prc protease in ExPEC-induced UTIs and the underlying mechanism.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The uropathogenic role of Prc was determined in a mouse model of UTIs. Using global quantitative proteomic analyses, we revealed that the expression of FliC and other outer membrane-associated proteins was altered by Prc deficiency. Comparative transcriptome analyses identified that Prc deficiency affected expression of the flagellar regulon and genes that are regulated by five extracytoplasmic signaling systems.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>A mutant ExPEC with a <jats:italic>prc<\/jats:italic> deletion was attenuated in bladder and kidney colonization. Global quantitative proteomic analyses of the <jats:italic>prc<\/jats:italic> mutant and wild-type ExPEC strains revealed significantly reduced flagellum expression in the absence of Prc, consequently impairing bacterial motility. The <jats:italic>prc<\/jats:italic> deletion triggered downregulation of the flhDC operon encoding the master transcriptional regulator of flagellum biogenesis. Overexpressing <jats:italic>flhDC<\/jats:italic> restored the <jats:italic>prc<\/jats:italic> mutant\u2019s motility and ability to colonize the UT, suggesting that the impaired motility is responsible for attenuated UT colonization of the mutant. Further comparative transcriptome analyses revealed that Prc deficiency activated the \u03c3<jats:sup>E<\/jats:sup> and RcsCDB signaling pathways. These pathways were responsible for the diminished <jats:italic>flhDC<\/jats:italic> expression. Finally, the activation of the RcsCDB system was attributed to the intracellular accumulation of a known Prc substrate Spr in the <jats:italic>prc<\/jats:italic> mutant. Spr is a peptidoglycan hydrolase and its accumulation destabilizes the bacterial envelope.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We demonstrated for the first time that Prc is essential for full ExPEC virulence in UTIs. Our results collectively support the idea that Prc is essential for bacterial envelope integrity, thus explaining how Prc deficiency results in an attenuated ExPEC.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12929-019-0605-y","type":"journal-article","created":{"date-parts":[[2020,1,3]],"date-time":"2020-01-03T07:03:22Z","timestamp":1578035002000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["The role of the bacterial protease Prc in the uropathogenesis of extraintestinal pathogenic Escherichia coli"],"prefix":"10.1186","volume":"27","author":[{"given":"Wen-Chun","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Yen","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiunn-Jong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Cheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Hung","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Shi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4615-094X","authenticated-orcid":false,"given":"Ching-Hao","family":"Teng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,3]]},"reference":[{"issue":"1","key":"605_CR1","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1093\/infdis\/jiv429","volume":"213","author":"JT Poolman","year":"2016","unstructured":"Poolman JT, Wacker M. 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