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

Dustin 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

bioRxiv : the preprint server for biology · 2025

PubMed ↗ DOI ↗ PMC full text ↗

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.

Linked datasets 1

GSE284636 GSE · via ncbi_elink
GEO ↗

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

Mus musculus

178 data files
FileTypeSize
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E_HA_INPUT_1_S71_L005_R1_001.fastq.gz OTHER 437.4 MB
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M23_FLAG_INPUT_1_S77_L005_R1_001.fastq.gz OTHER 378.5 MB
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M23_FLAG_INPUT_3_S126_L007_R1_001.fastq.gz OTHER 475.9 MB
M23_FLAG_IP_1_S70_L005_R1_001.fastq.gz OTHER 1.4 GB
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M23_HA_IP_1_S69_L005_R1_001.fastq.gz OTHER 1.1 GB
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M3_INPUT_3_S124_L007_R1_001.fastq.gz OTHER 408.8 MB
M3_IP_1_S68_L005_R1_001.fastq.gz OTHER 370.5 MB
M3_IP_2_S87_L006_R1_001.fastq.gz OTHER 578.7 MB
M3_IP_3_S117_L007_R1_001.fastq.gz OTHER 570.3 MB
SRR31773483_GSM8689720 OTHER 461.0 MB
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SRR31773487_GSM8689716 OTHER 434.0 MB
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SRR31773489 OTHER 493.6 MB
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SRR31773553_GSM8689650 OTHER 484.0 MB
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SRR31773555_GSM8689648 OTHER 354.0 MB
SRR31773556_GSM8689647 OTHER 378.0 MB
SRR31773557_GSM8689646 OTHER 1.4 GB
SRR31773558_GSM8689645 OTHER 458.0 MB
SRR31773559_GSM8689644 OTHER 1.1 GB
SRR31773560_GSM8689643 OTHER 482.0 MB
SRR31773561_GSM8689642 OTHER 370.0 MB
SRR31773562_GSM8689641 OTHER 460.0 MB
SRR31773563_GSM8689640 OTHER 535.0 MB
SRR31773564_GSM8689639 OTHER 430.0 MB
SRR31773565_GSM8689638 OTHER 555.0 MB
SRR31773566_GSM8689637 OTHER 490.0 MB
SRR31773567_GSM8689636 OTHER 531.0 MB
SRR31773568_GSM8689635 OTHER 437.0 MB
SRR31773569_GSM8689634 OTHER 445.0 MB

Potentially related datasets 1

These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.

Accession Source Title
GSE284636 GSE · GEO GEO ↗ Short 5’ UTRs serve as a marker for mRNA translation inhibition by the IFIT2-IFIT3 antiviral complex

Analysis pipelines 1

Pipeline Assay Steps Dataset
GSE284636 eCLIP Data Processing geo_data_processing eCLIP 10 GSE284636
Funding 10 grants
Grant Funder
U24 HG009889 NHGRI NIH HHS (United States)
R01 HG004659 NHGRI NIH HHS (United States)
U24 HG011735 NHGRI NIH HHS (United States)
RF1 MH126719 NIMH NIH HHS (United States)
R01 HG011864 NHGRI NIH HHS (United States)
R35 GM144121 NIGMS NIH HHS (United States)
R35 GM133633 NIGMS NIH HHS (United States)
R00 HG009530 NHGRI NIH HHS (United States)
K22 AI119017 NIAID NIH HHS (United States)
T32 GM133351 NIGMS NIH HHS (United States)