The IFIT2–IFIT3 antiviral complex targets short 5’ untranslated regions on viral mRNAs for translation inhibition
Year: 2025
Type: article
Abstract: Recognition of foreign RNA is critical for the innate immune response to viruses. Interferon (IFN)-induced proteins with tetratricopeptide repeats (IFIT) 2 and 3 are highly upregulated following viral infection, but mechanistic insight into their antiviral role is lacking. Here we demonstrate that short 5' untranslated regions (UTRs), a characteristic of many viral mRNAs, can serve as a molecular pattern for innate immune recognition via IFIT2 and IFIT3. Structure determination of the IFIT2-IFIT3 complex at 3.2 Å using cryo-EM reveals a domain-swapped heterodimer that is required for recognition of the viral mRNA 5' end, translation inhibition and antiviral activity. Critically, viral or host 5' UTR lengths less than 50 nucleotides are necessary and sufficient to enable 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.
Source: Nature Microbiology
Authors: Dustin R. Glasner, Candace Todd, Brian Cook, Agustina D’Urso, Shivani Khosla, Elena Estrada, Jaxon D. Wagner, Mason D. Bartels, Chuan-Tien Hung, Pierce Ford, Jordan Prych, Kathryn S. Hatch, Brian A. Yee, Kaori M. Ego, Qishan Liang, Sarah R. Holland, James Brett Case, Kevin D. Corbett, Michael S. Diamond, Benhur Lee, Gene W. Yeo, Mark A. Herzik, Eric L. Van Nostrand, Matthew D. Daugherty
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, Burroughs Wellcome Fund, Yale University, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Defense Advanced Research Projects Agency, National Institute of Mental Health, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
Awards: G1632510292, G1755907644, G178164249, G192417208, G2019986479, Pathways in Biological Sciences Training Program, G2744059635, G3141942385, G3350646238, G405766372, G4110149347, G4257690818, Ribo-STAMPEDE: novel tools for molecular profiling of brain cell types, STAMP technology to enable single-cell and isoform-sensitive detection of RBP sites, Molecular mechanisms of nucleic acid recognition and maintenance in meiosis and innate immunity, G6163367702, G617226994, Robust, high-throughput identification of RNA processing regulators and regulatory networks genome-wide, G647031076, G650072410, G6939118823, Functional RNA elements in the human genome, G7056609824, G7209641628, G7749265786, G8189091010, G8387866041, G8429758474, G860272616, Pathogen-driven evolution of innate antiviral defense mechanisms, G9000034628, G9000040234, G9000045478, G9000082385, G9000171507, G9000220848, G9000224292, G9000278390, G9000348009, Technology Development Coordinating Center
OpenAlex ID: W4415208943