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Previous studies have reported that FNN and FNP strains produce AI-2 and have proposed that AI-2\u2013mediated quorum sensing contributes to biofilm formation and virulence. However, the distribution and functional relevance of AI-2 across all subspecies have not been systematically examined. Here, we show that AI-2 production is restricted to FNA strains. Genomic analysis revealed that FNN and FNV lack\n                      <jats:italic toggle=\"yes\">luxS<\/jats:italic>\n                      , whereas FNP carries a disrupted\n                      <jats:italic toggle=\"yes\">luxS<\/jats:italic>\n                      homolog. Consistent with these findings, AI-2 bioassays using the\n                      <jats:italic toggle=\"yes\">Vibrio harveyi<\/jats:italic>\n                      BB170 reporter detected AI-2 exclusively in FNA strains. Deletion of\n                      <jats:italic toggle=\"yes\">luxS<\/jats:italic>\n                      in FNA abolished AI-2 production, but resulted in minimal transcriptional changes, and exogenous AI-2 failed to elicit strong transcriptional responses in non-producing subspecies. These results demonstrate that AI-2 production in\n                      <jats:italic toggle=\"yes\">F. nucleatum<\/jats:italic>\n                      is subspecies-specific and uncoupled from quorum sensing. Our findings revise current assumptions regarding AI-2\u2013mediated communication in\n                      <jats:italic toggle=\"yes\">F. nucleatum<\/jats:italic>\n                      and reveal previously unrecognized metabolic divergence within the species complex.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Periodontitis affects nearly half of adults in the United States and remains a leading cause of tooth loss worldwide.\n                      <jats:italic toggle=\"yes\">Fusobacterium nucleatum<\/jats:italic>\n                      is a central member of oral biofilms and has also been linked to adverse pregnancy outcomes and colorectal cancer. Although autoinducer-2 (AI-2)-mediated quorum sensing has been proposed to contribute to its biofilm formation and virulence, our study demonstrates that AI-2 production is confined to subsp.\n                      <jats:italic toggle=\"yes\">animalis<\/jats:italic>\n                      and is absent in other subspecies. Moreover, AI-2 does not function as a conserved quorum-sensing regulator in this species. These findings fundamentally revise prevailing assumptions about AI-2 signaling in\n                      <jats:italic toggle=\"yes\">F. nucleatum<\/jats:italic>\n                      and suggest that subspecies-specific metabolic traits, rather than universal quorum sensing, may underlie ecological adaptation and host association.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jb.00223-26","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:53:25Z","timestamp":1784555605000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["AI-2 production in\n                    <i>Fusobacterium nucleatum<\/i>\n                    is subspecies-specific and uncoupled from quorum sensing"],"prefix":"10.1128","volume":"208","author":[{"given":"Bibek","family":"G C","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03gds6c39","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology & Molecular Genetics, the University of Texas Health Science Center","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqi","family":"Xu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03gds6c39","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology & Molecular Genetics, the University of Texas Health Science Center","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Truman","family":"Tran","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03gds6c39","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology & Molecular Genetics, the University of Texas Health Science Center","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5700-7188","authenticated-orcid":true,"given":"Chenggang","family":"Wu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03gds6c39","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology & Molecular Genetics, the University of Texas Health Science Center","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2006.01.003"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03960"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.181.17.5135-5139.1999"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2010.07455.x"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.21.012704.131001"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.5.3431-3434.2001"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.4.1972-1979.2003"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/jobm.201700010"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.057182-0"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00402-07"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-148-3-763"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.66.3.486-505.2002"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0757.2006.00187.x"},{"key":"e_1_3_4_15_2","first-page":"25","article-title":"Fusobacterium nucleatum in periodontal health and disease","volume":"13","author":"Signat B","year":"2011","unstructured":"Signat B, Roques C, Poulet P, Duffaut D. 2011. 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