Induction of an Alternative mRNA 5′ Leader Enhances Translation of the Ciliopathy Gene Inpp5e and Resistance to Oncolytic Virus Infection
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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.
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- Authors
- Hoang, H.-D., Graber, T. E., Jia, J.-J., Vaidya, N., Gilchrist, V. H., Xiang, X., Li, W., Cowan, K. N., Gkogkas, C. G., Jaramillo, M., Jafarnejad, S. M., & Alain, T.
- Affiliations
- University of Ottawa (CA)
- Children's Hospital of Eastern Ontario (CA)
- Rutgers New Jersey Medical School (US)
- University of Edinburgh (GB)
- Institut National de la Recherche Scientifique (CA)
- Queen's University Belfast (GB)
- Corresponding author
- Alain, Tommy
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 29
- Issue
- 12
- Pages
- 4010-4023.e5
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2996574778
- Cited by
- 18
- References
- 3
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 2 · 2020: 5
- FWCI
- 0.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- EspaceINRS (National Institute for Scientific Research (Canada)) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Natural Sciences and Engineering Research Council of Canada
- Terry Fox Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- INPP5E, upstream open reading frames, translational regulation, antiviral immunity, breast cancer, 4T1 cells, herpes simplex virus type 1, reovirus, vaccinia virus, viral attachment, inositol polyphosphate 5-phosphatase, host-virus interaction
- MeSH terms
- Phosphoinositide 5-Phosphatases, Animals, Female, Phosphoric Monoester Hydrolases, Ribosomes, RNA, Messenger, Protein Biosynthesis, Mammary Neoplasms, Animal, Open Reading Frames, 5' Untranslated Regions, Oncolytic Virotherapy, Oncolytic Viruses, Mice
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