Induction of an alternative 5’ leader enhances translation of Inpp5e and resistance to oncolytic virus infection

ABSTRACT Residual cell-intrinsic innate immunity in cancer cells hampers infection with oncolytic viruses. mRNA translation is an important component of innate immunity, yet the targeted cellular mRNAs remain ill-defined. We characterized the translatome 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 were translationally de-repressed mRNAs involved in ciliary homeostasis including Inpp5e , encoding an inositol 5-phosphatase that modifies lipid second messenger signalling. Translationally repressed in the uninfected condition, viral infection induced expression of an Inpp5e mRNA variant that lacks repressive upstream open reading frames (uORFs) within its 5’ leader and is consequently 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 ciliary proteins such as INPP5E to the cellular antiviral response.