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Here, we investigate the function of FliS in the Lyme disease spirochete <jats:styled-content style=\"fixed-case\">\n<jats:italic>Borrelia burgdorferi<\/jats:italic>\n<\/jats:styled-content>. Using loss\u2010of\u2010function studies, combined with biochemical assays and cryo\u2010electron tomography, we demonstrate that FliS deletion selectively reduces FlaB expression, the major flagellin protein, resulting in non\u2010motile mutants with defective flagellar filaments. Mechanistically, we show that FlaB interacts with both FliS and FliW, the latter being an allosteric repressor of the RNA\u2010binding protein CsrA, which inhibits FlaB translation. These four components form a regulatory circuit that fine\u2010tunes FlaB levels and flagellar assembly via a partner\u2010switching mechanism. Deletion of <jats:italic>fliS<\/jats:italic> disrupts FlaB secretion, leading to its cytoplasmic accumulation, sequestration of FliW, and subsequent release of CsrA to suppress FlaB synthesis. Accumulation of cytoplasmic FlaB also triggers its degradation to prevent toxicity. Our findings reveal a post\u2010transcriptional regulatory mechanism governing flagellar assembly in <jats:styled-content style=\"fixed-case\">\n<jats:italic>B. burgdorferi<\/jats:italic>\n<\/jats:styled-content>, an evolutionary outlier that lacks the canonical transcriptional cascade controlling flagellar biosynthesis in most bacteria.<\/jats:p>","DOI":"10.1111\/mmi.15380","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T11:02:03Z","timestamp":1749726123000},"page":"173-187","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Flagellin\u2010Specific Chaperone <scp>FliS<\/scp> of <scp><i>Borrelia\u00a0burgdorferi<\/i><\/scp> Controls the Cytoplasmic Pool of Flagellins at the Level of Translation Initiation, Secretion, and Proteolysis"],"prefix":"10.1111","volume":"124","author":[{"given":"Ching Wooen","family":"Sze","sequence":"first","affiliation":[{"name":"Department of Oral Craniofacial Molecular Biology Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oral Craniofacial Molecular Biology Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Lynch","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology Cornell University  Ithaca New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangbiao","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis Yale School of Medicine  New Haven Connecticut USA"},{"name":"Microbial Sciences Institute, Yale University  West Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis Yale School of Medicine  New Haven Connecticut USA"},{"name":"Microbial Sciences Institute, Yale University  West Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian R.","family":"Crane","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology Cornell University  Ithaca New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1872-4870","authenticated-orcid":false,"given":"Chunhao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oral Craniofacial Molecular Biology Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,9]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1180"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2014.11.009"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-012373944-5.00047-X"},{"issue":"11552","key":"e_1_2_9_6_1","first-page":"1","article-title":"FliS\/Flagellin\/FliW Heterotrimer Couples Type III Secretion and Flagellin Homeostasis","volume":"8","author":"Altegoer F.","year":"2018","journal-title":"Scientific Reports"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1602425113"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2001.4597"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.01913-06"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.36.041602.134359"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1887"},{"key":"e_1_2_9_12_1","first-page":"1","article-title":"Type III Secretion Systems: The Bacterial Flagellum and the Injectisome","volume":"370","author":"Diepold A.","year":"2015","journal-title":"Philosophical Transactions of the Royal Society of London. 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