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

doi:10.1016/j.celrep.2019.11.072

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

Cell Rep. 2019 Dec 17;29(12):4010-4023.e5. doi: 10.1016/j.celrep.2019.11.072.

Authors

Affiliations

¹ 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.
² 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.
³ Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.
⁴ 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.
⁵ Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Newark, NJ 07101, USA.
⁶ 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.
⁷ Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.
⁸ INRS Institut Armand-Frappier Research Centre, Laval, QC H7V 1B7, Canada.
⁹ Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast BT9 7AE, UK.
¹⁰ 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. Electronic address: [email protected].

PMID: 31851930
DOI: 10.1016/j.celrep.2019.11.072

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.

Keywords: INPP5E; RNA variant; alternative splicing; breast cancer; ciliopathy; isoform switch; oncolytic virus; ribosome profiling; translation; uORF.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

5' Untranslated Regions / genetics*
Animals
Female
Mammary Neoplasms, Animal / genetics
Mammary Neoplasms, Animal / metabolism
Mammary Neoplasms, Animal / therapy*
Mammary Neoplasms, Animal / virology
Mice
Oncolytic Virotherapy*
Oncolytic Viruses / pathogenicity*
Open Reading Frames
Phosphoric Monoester Hydrolases / genetics
Phosphoric Monoester Hydrolases / metabolism*
Protein Biosynthesis*
RNA, Messenger / genetics
RNA, Messenger / metabolism*
Ribosomes / metabolism

Substances

5' Untranslated Regions
RNA, Messenger
Phosphoric Monoester Hydrolases
phosphoinositide 5-phosphatase