Induction of an Alternative mRNA 5′ Leader Enhances Translation of the Ciliopathy Gene Inpp5e and Resistance to Oncolytic Virus Infection
Huy-Dung Hoang,
Tyson E. Graber,
Jian-Jun Jia,
Nasana Vaidya,
Victoria H. Gilchrist,
Xiao Xiang,
Wencheng Li,
Kyle N. Cowan,
Christos G. Gkogkas,
Maritza Jaramillo,
Seyed Mehdi Jafarnejad,
Tommy Alain
Affiliations
Huy-Dung Hoang
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Tyson E. Graber
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada; Department of Biochemistry and Goodman Cancer Center, McGill University, Montreal, QC H3A 1A3, Canada
Jian-Jun Jia
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
Nasana Vaidya
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
Victoria H. Gilchrist
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Xiao Xiang
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Wencheng Li
Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Newark, NJ 07101, USA
Kyle N. Cowan
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Department of Surgery, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON K1H 8L1, Canada
Christos G. Gkogkas
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK
Maritza Jaramillo
INRS Institut Armand-Frappier Research Centre, Laval, QC H7V 1B7, Canada
Seyed Mehdi Jafarnejad
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Belfast BT9 7AE, UK
Tommy Alain
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Corresponding author
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
