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How RIG\u2010I\u2010deficient vertebrates preserve recognition of RIG\u2010I\u2010associated viral RNA remains poorly understood. Here, we show that MDA5 from the large yellow croaker (\n                    <jats:italic>Larimichthys crocea<\/jats:italic>\n                    ,\n                    <jats:italic>Lc<\/jats:italic>\n                    ), a teleost species lacking RIG\u2010I, recognizes both 5\u2032\u2010triphosphate dsRNA (5\u2032ppp\u2010dsRNA), the canonical ligand of RIG\u2010I, and long dsRNA, the classical ligand of MDA5. Its C\u2010terminal domain (CTD) is essential for the recognition of both ligands, with residues specifically required for sensing the 5\u2032ppp moiety. Structural modeling, molecular dynamics simulations, and mutational validation support a model in which a flexible RNA\u2010capping loop in the CTD confers\n                    <jats:italic>Lc<\/jats:italic>\n                    MDA5 a conformational plasticity, allowing the CTD to cap the 5\u2032ppp\u2010dsRNA terminus for RIG\u2010I\u2010like recognition or orienting the CTD parallel to long\u2010dsRNA axis for canonical MDA5 recognition. Disruption of 5\u2032ppp recognition impaired\n                    <jats:italic>Lc<\/jats:italic>\n                    MDA5\u2010mediated antiviral activity against a RIG\u2010I\u2010sensitive virus. Downstream,\n                    <jats:italic>Lc<\/jats:italic>\n                    MDA5 signals through an integrated MAVS\u2013STING\u2013TBK1\/IRF3 axis to drive type I IFN responses to both RNA ligands. Our findings reveal an unexpectedly\u00a0flexible architecture of vertebrate cytosolic RNA sensing in which a single RLR combines ligand\u2010recognition and signaling properties classically partitioned between RIG\u2010I and MDA5.\n                  <\/jats:p>","DOI":"10.1002\/advs.78318","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:47:05Z","timestamp":1792036025000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Fish MDA5 Integrates Canonical RIG\u2010I and MDA5 Ligand Recognition"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1084-0121","authenticated-orcid":false,"given":"Wenxing","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Mariculture Breeding Key Laboratory of Marine Biotechnology of Fujian Province College of Marine Sciences Fujian Agriculture and Forestry University  Fuzhou 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1997-0889","authenticated-orcid":false,"given":"\u00c1lvaro","family":"Fern\u00e1ndez Montero","sequence":"additional","affiliation":[{"name":"Grupo de investigaci\u00f3n en acuicultura (GIA) IU\u2010ECOAQUA Universidad De Las Palmas De Gran Canaria  Las Palmas Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangtao","family":"Gao","sequence":"additional","affiliation":[{"name":"College of Biomedical Sciences Fujian Agriculture and Forestry University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingqun","family":"Ao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Mariculture Breeding Key Laboratory of Marine Biotechnology of Fujian Province College of Marine Sciences Fujian Agriculture and Forestry University  Fuzhou 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