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Here, we demonstrate that short 5\u2019 untranslated regions (UTRs), a characteristic of many viral mRNAs, can also serve as a molecular pattern for innate immune recognition via the interferon-induced proteins IFIT2 and IFIT3. The IFIT2-IFIT3 heterodimer, formed through an intricate domain swap structure resolved by cryo-EM, mediates viral mRNA 5\u2019 end recognition, translation inhibition, and ultimately antiviral activity. Critically, 5\u2019 UTR lengths &lt;50 nucleotides are necessary and sufficient to sensitize an mRNA to translation inhibition by the IFIT2-IFIT3 complex. Accordingly, diverse viruses whose mRNAs contain short 5\u2019 UTRs, such as vesicular stomatitis virus and parainfluenza virus 3, are sensitive to IFIT2-IFIT3-mediated antiviral activity. Our work thus reveals a pattern of antiviral nucleic acid immune recognition that takes advantage of the inherent constraints on viral genome size.<\/jats:p>","DOI":"10.1101\/2025.02.11.637299","type":"posted-content","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T23:05:17Z","timestamp":1739315117000},"source":"Crossref","is-referenced-by-count":2,"title":["Short 5\u2019 UTRs serve as a marker for viral mRNA translation inhibition by the IFIT2-IFIT3 antiviral complex"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9821-6683","authenticated-orcid":false,"given":"Dustin 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