Short 5' UTRs serve as a marker for viral mRNA translation inhibition by the IFIT2-IFIT3 antiviral complex

Glasner, D. R.; Todd, C.; Cook, B.; D'Urso, A.; Khosla, S.; Estrada, E.; Wagner, J. D.; Bartels, M. D.; Ford, P.; Prych, J.; Hatch, K.; Yee, B. A.; Ego, K. M.; Liang, Q.; Holland, S. R.; Case, J. B.; Corbett, K. D.; Diamond, M. S.; Yeo, G. W.; Herzik, M. A.; Van Nostrand, E. L.; Daugherty, M. D.

doi:10.1101/2025.02.11.637299

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bioRxiv · 10.1101/2025.02.11.637299

Short 5' UTRs serve as a marker for viral mRNA translation inhibition by the IFIT2-IFIT3 antiviral complex

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Abstract

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.

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Glasner, D. R., Todd, C., Cook, B., D'Urso, A., Khosla, S., Estrada, E., Wagner, J. D., Bartels, M. D., Ford, P., Prych, J., Hatch, K., Yee, B. A., Ego, K. M., Liang, Q., Holland, S. R., Case, J. B., Corbett, K. D., Diamond, M. S., Yeo, G. W., Herzik, M. A., Van Nostrand, E. L., Daugherty, M. D.. 2025-02-11. Short 5' UTRs serve as a marker for viral mRNA translation inhibition by the IFIT2-IFIT3 antiviral complex. https://doi.org/10.1101/2025.02.11.637299

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