Influenza virus repurposes the antiviral protein IFIT2 to promote translation of viral mRNAs
- 24 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Microbiology
- Vol. 5 (12), 1490-1503
- https://doi.org/10.1038/s41564-020-0778-x
Abstract
Cells infected by influenza virus mount a large-scale antiviral response and most cells ultimately initiate cell-death pathways in an attempt to suppress viral replication. We performed a CRISPR–Cas9-knockout selection designed to identify host factors required for replication after viral entry. We identified a large class of presumptive antiviral factors that unexpectedly act as important proviral enhancers during influenza virus infection. One of these, IFIT2, is an interferon-stimulated gene with well-established antiviral activity but limited mechanistic understanding. As opposed to suppressing infection, we show in the present study that IFIT2 is instead repurposed by influenza virus to promote viral gene expression. CLIP‐seq demonstrated that IFIT2 binds directly to viral and cellular messenger RNAs in AU‐rich regions, with bound cellular transcripts enriched in interferon‐stimulated mRNAs. Polysome and ribosome profiling revealed that IFIT2 prevents ribosome pausing on bound mRNAs. Together, the data link IFIT2 binding to enhanced translational efficiency for viral and cellular mRNAs and ultimately viral replication. Our findings establish a model for the normal function of IFIT2 as a protein that increases translation of cellular mRNAs to support antiviral responses and explain how influenza virus uses this same activity to redirect a classically antiviral protein into a proviral effector.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (T32GM07215)
- National Science Foundation (DGE-1747503)
- Deutsche Forschungsgemeinschaft (GSC-4, Spemann Graduate School, SFB 1160, project 13)
- Ministry for Science, Research and Arts of the State of Baden-Wuerttemberg
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (U19AI106754, HHSN272201400008C, U19AI135972, R01AI118938, R01AI104972, R21AI125897, R01AI125271)
- Burroughs Wellcome Fund (Investigator in the Pathogenesis of Infectious Disease)
- UW2020:WARF Discovery InitiativeShaw Scientist Award from the Great Milwaukee Foundation
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