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

Huy-Dung Hoang, Tyson Ernst Graber, Jian-Jun Jia, Nasana Vaidya, Victoria Heather Gilchrist, Wencheng Li, Christos Gkogkas, Maritza Jaramillo, Seyed Mehdi Jafarnejad, Tommy Alain

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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.
Original languageEnglish
Pages (from-to) 4010-4023.e5
JournalCell Reports
Volume29
Issue number12
Early online date17 Dec 2019
DOIs
Publication statusEarly online date - 17 Dec 2019

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