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Autoinducer-2 (AI-2) is unique among QS signals in that its production is tightly linked to central metabolism, raising fundamental questions about the boundary between metabolic and signaling functions. In\n                      <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                      , AI-2 coordinates collective behaviors through the\n                      <jats:italic toggle=\"yes\">lsr<\/jats:italic>\n                      operon, whose expression is controlled not only by the AI-2-responsive repressor LsrR but also by the cAMP receptor protein (CRP), placing it at the intersection of carbon sensing and population-level signaling. While inhibition of\n                      <jats:italic toggle=\"yes\">lsr<\/jats:italic>\n                      expression by PTS sugars was previously established, we show that non-PTS sugars similarly suppress\n                      <jats:italic toggle=\"yes\">lsr<\/jats:italic>\n                      expression through CRP, further decoupling QS activation from cell density and coupling it to carbon source availability. Genomic analysis across\n                      <jats:italic toggle=\"yes\">Enterobacteriaceae<\/jats:italic>\n                      reveals that CRP binding sites in the\n                      <jats:italic toggle=\"yes\">lsr<\/jats:italic>\n                      promoter are broadly conserved, indicating that metabolic modulation of AI-2 signaling is an ancestral regulatory feature. Using a FRET-based biosensor, we further show that AI-2 uptake modulates intracellular cAMP levels similarly to non-PTS carbon transport, suggesting AI-2 may have originally functioned as a nutrient substrate. Additionally, we isolated soil- and phyllosphere-associated bacteria capable of utilizing AI-2 as a sole carbon source. Interestingly, this capacity seems to have evolved independently from the ability to produce and metabolize AI-2 through the LuxS\/Lsr pathway. Overall, our findings reveal an underappreciated metabolic basis of AI-2 QS and suggest that, in some species, nutrient utilization and intercellular signaling may have diverged from a common ancestral pathway.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Quorum sensing allows bacteria to coordinate collective behaviors by detecting secreted signaling molecules, yet the evolutionary origins of these systems remain poorly understood. AI-2, one of the most broadly conserved bacterial signals, is derived from central metabolism and processed by machinery in\n                        <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                        that strikingly resembles a sugar utilization system. Here, we show that nutrient availability overrides cell density as the primary determinant of AI-2 responsiveness, that this regulatory logic is conserved among\n                        <jats:italic toggle=\"yes\">Enterobacteriaceae<\/jats:italic>\n                        genomes, and that environmental bacteria can grow on AI-2 as a sole carbon source. These findings reframe AI-2 as a signal embedded within, and potentially evolved from, nutrient-sensing pathways, with direct implications for understanding how byproducts of cellular metabolism can acquire signaling functions.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/aem.01160-26","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:00:48Z","timestamp":1791205248000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Autoinducer-2 functions as both a quorum-sensing and metabolic signal in\n                    <i>Escherichia coli<\/i>"],"prefix":"10.1128","author":[{"given":"No\u00e9mie","family":"Godrie","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05r7n9c40","id-type":"ROR","asserted-by":"publisher"}],"name":"Max Planck Institute for Terrestrial Microbiology and Center for 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