Induction of an Alternative mRNA 5′ Leader Enhances Translation of the Ciliopathy Gene Inpp5e and Resistance to Oncolytic Virus Infection

Abstract

Summary: 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. : Resistance of tumors to “oncolytic” viral therapies can be mediated by changes in cellular mRNA translation upon infection. Hoang et al. explore translatomes of infected breast cancer cells, identifying Inpp5e as a regulated viral resistance gene. In this context, transcript switching favors an Inpp5e mRNA variant with increased translational output. Keywords: oncolytic virus, ribosome profiling, translation, uORF, INPP5E, ciliopathy, RNA variant, isoform switch, alternative splicing, breast cancer