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Influenza virus repurposes the antiviral protein IFIT2 to promote translation of viral mRNAs

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 following viral entry. We identified a large class of presumptive antiviral factors that unexpectedly act as important pro-viral 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 here that IFIT2 is instead repurposed by influenza virus to promote viral gene expression. CLIP‐seq demonstrated that IFIT2 binds directly to viral and cellular mRNAs 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 pro-viral effector.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196010 | GEO | 2022/02/03

REPOSITORIES: GEO

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Influenza virus repurposes the antiviral protein IFIT2 to promote translation of viral mRNAs

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