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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,4,22]]},"abstract":"<jats:p>\n                    TonB-dependent signal transduction is a versatile mechanism observed in gram-negative bacteria that integrates energy-dependent substrate transport with signal relay. In\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    , the TonB\u2013ExbBD motor complex energizes the TonB-dependent outer membrane transporter FecA, facilitating ferric citrate import. FecA also acts as a sensor, transmitting signals to the cytoplasmic membrane protein FecR, which eventually activates the cytoplasmic sigma factor FecI, driving transcription of the\n                    <jats:italic>fec<\/jats:italic>\n                    operon. Building on our previous finding that FecR undergoes functional maturation through a three-step cleavage process [T. Yokoyama\n                    <jats:italic>et al., J. Biol. Chem.<\/jats:italic>\n                    <jats:bold>296<\/jats:bold>\n                    , 100673 (2021)], we here describe the complete mechanism of FecR-mediated ferric citrate signaling involving FecA and TonB. The cleavage cascade begins with FecR autoproteolysis prior to membrane integration. The soluble C-terminal domain (CTD) fragment of FecR is cotranslocated with the N-terminal domain (NTD) fragment through a twin-arginine translocation (Tat) system\u2013mediated process. In the periplasm, the interaction between the CTD and NTD fragments prevents further cleavage. Binding of ferric citrate induces a conformational change in FecA, exposing its TonB box to the periplasmic space. This structural alteration is transmitted to the interacting FecR CTD via the motor function of TonB, resulting in the release of the CTD blockage from the NTD. Consequently, the successive cleavage of FecR\u2019s NTD is initiated, culminating in the ferric citrate signal\u2013induced activation of\n                    <jats:italic>fec<\/jats:italic>\n                    gene expression. Our findings reveal that the regulation of FecR cleavage, controlled by the TonB\u2013FecA axis, plays a central role in the bacterial response to ferric citrate signals.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2500366122","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T11:47:36Z","timestamp":1744890456000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Cleavage cascade of the sigma regulator FecR orchestrates TonB-dependent signal transduction"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3122-6822","authenticated-orcid":false,"given":"Tatsuhiko","family":"Yokoyama","sequence":"first","affiliation":[{"name":"Department of Microbiology, Graduate School of Medicine, Gifu University","place":["Gifu, 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