The IFIT2–IFIT3 antiviral complex targets short 5’ untranslated regions on viral mRNAs for translation inhibition
Year: 2025
Type: article
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.
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, Consequences of IFIT Gene Evolution on Species-Specific Antiviral Immunity, 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, G6163367702, G617226994, Robust, high-throughput identification of RNA processing regulators and regulatory networks genome-wide, G6939118823, Functional RNA elements in the human genome, G7056609824, G7209641628, G7749265786, G8189091010, G860272616, G9000045478, G9000082385, Molecular mechanisms of nucleic acid recognition and maintenance in meiosis and innate immunity, A comprehensive binding and functional map of human RNA-binding proteins, Pathways in Biological Sciences Training Program, Technology Development Coordinating Center, Evolution of innate antiviral defense mechanisms and other microbe-driven genetic innovations, Understanding the Tropism and Pathogenesis of Pararubulaviruses
OpenAlex ID: W4415208943