biostudies-literatureUnknownGlasner DRNIAID NIH HHSNIMH NIH HHSNHGRI NIH HHSNIGMS NIH HHSRecognition of "non-self" nucleic acids, including cytoplasmic dsDNA, dsRNA, or mRNAs lacking proper 5' cap structures, is critical for the innate immune response to viruses. Here, we demonstrate that short 5' 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' end recognition, translation inhibition, and ultimately antiviral activity. Critically, 5' UTR lengths <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 5bioRxiv : the preprint server for biology2025.02.11.637299https://www.ebi.ac.uk/biostudies/studies/S-EPMC11844544biostudies-literatureShort 5' UTRs serve as a marker for viral mRNA translation inhibition by the IFIT2-IFIT3 antiviral complex.PMC11844544K22 AI119017U24 HG011735R00 HG009530R01 HG011864RF1 MH126719T32 GM133351R35 GM133633R01 HG004659U24 HG009889R35 GM144121Diamond MSCase JBEgo KMHerzik MAYeo GWEstrada ECook BCorbett KDFord PDaugherty MDWagner JDPrych JD'Urso AVan Nostrand ELKhosla SHolland SRBartels MDYee BATodd CHatch KGlasner DRLiang QfalseShort 5' UTRs serve as a marker for viral mRNA translation inhibition by the IFIT2-IFIT3 antiviral complex.Recognition of "non-self" nucleic acids, including cytoplasmic dsDNA, dsRNA, or mRNAs lacking proper 5' cap structures, is critical for the innate immune response to viruses. Here, we demonstrate that short 5' 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' end recognition, translation inhibition, and ultimately antiviral activity. Critically, 5' UTR lengths <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 52025-01-01T00:00:00Z2025 Feb2026-04-08T19:23:49.926Z2025-04-04T09:08:11.637ZS-EPMC118445443999037010.1101/2025.02.11.637299