Abstract
Residual cell-intrinsic innate immunity in cancer cells hampers infection with oncolytic viruses. Translational control of mRNA is an important feature of innate immunity, yet the identity of translationally regulated mRNAs functioning in host defense remains ill-defined. We report the translatomes of resistant murine "4T1" breast cancer cells infected with three of the most clinically advanced oncolytic viruses: herpes simplex virus 1, reovirus, and vaccinia virus. Common among all three infections are translationally de-repressed mRNAs, including Inpp5e, encoding an inositol 5-phosphatase that modifies lipid second messenger signaling. We find that viral infection induces the expression of an Inpp5e mRNA variant that lacks repressive upstream open reading frames (uORFs) within its 5' leader and is efficiently translated. Furthermore, we show that INPP5E contributes to antiviral immunity by altering virus attachment. These findings uncover a role for translational control through alternative 5' leader expression and assign an antiviral function to the ciliopathy gene Inpp5e.
Highlights
Mammalian cells possess a sophisticated cell-intrinsic innate antiviral program that is activated upon infection
In addition to the m7G cap structure, which helps recruit eukaryotic initiation factors (eIFs), other cis-acting sequence elements that lie within 50 leaders, such as 50 terminal oligopyrimidine (TOP) motifs, upstream open reading frames, internal ribosome entry sites (IRESs), RNA-binding proteins (RBPs) binding sites, or localized secondary structure can govern the translational efficiency (TE) of mRNAs (Leppek et al, 2018; Shi and Barna, 2015)
During infection, signaling cascades that feed into mRNA translation such as phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin complex 1/(S6K or 4E-BP) and ERK/MNK/eIF4E were shown to enhance the translation of antiviral mRNAs, including IRF7 and ISG15 (Colina et al, 2008; Zakaria et al, 2018)
Summary
Mammalian cells possess a sophisticated cell-intrinsic innate antiviral program that is activated upon infection. Transcriptional induction of type I interferon expression (IFN-a and -b) and downstream interferon-stimulated genes (ISGs) is a major arm of the innate immune response to infection (Schneider et al, 2014). Another essential feature of this response is the mRNA translation arm of innate immunity, a reprogramming of protein synthesis to permit the expression of cellular antiviral proteins while concurrently thwarting the production of viral proteins (Walsh et al, 2013). Alternative mRNA transcription, splicing, and polyadenylation can indirectly modify translational output by altering 50 leaders and 30 UTRs, changing the composition of sequence elements that affect TE (Wang et al, 2016)
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