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TitleShort 5' UTRs serve as a marker for viral mRNA translation inhibition by the IFIT2-IFIT3 antiviral complex.
Journal, issue, pagesbioRxiv, Year 2025
Publish dateFeb 11, 2025
AuthorsDustin R Glasner / Candace Todd / Brian Cook / Agustina D'Urso / Shivani Khosla / Elena Estrada / Jaxon D Wagner / Mason D Bartels / Pierce Ford / Jordan Prych / Katie Hatch / Brian A Yee / Kaori M Ego / Qishan Liang / Sarah R Holland / James Brett Case / Kevin D Corbett / Michael S Diamond / Gene W Yeo / Mark A Herzik / Eric L Van Nostrand / Matthew D Daugherty /
PubMed AbstractRecognition 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 ...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 5' 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.
External linksbioRxiv / PubMed:39990370 / PubMed Central
MethodsEM (single particle)
Resolution3.22 Å
Structure data

48323

9mk9

EMDB-48323, PDB-9mk9:
Structure of the IFIT2-IFIT3 heterodimer from Mus musculus
Method: EM (single particle) / Resolution: 3.22 Å

Source
  • mus musculus (house mouse)
KeywordsANTIVIRAL PROTEIN / innate immune recognition / interferon-induced proteins / non-self nucleic acids

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