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Induction of an Alternative 5’ Leader Enhances Translation of Inpp5e and Resistance to Oncolytic Virus Infection

60 Pages Posted: 18 Jul 2019 Publication Status: Published

See all articles by Huy-Dung Hoang

Huy-Dung Hoang

University of Ottawa - Children's Hospital of Eastern Ontario Research Institute (CHEO)

Tyson Ernst Graber

University of Ottawa - Children's Hospital of Eastern Ontario Research Institute (CHEO)

Jian-Jun Jia

University of Ottawa - Children's Hospital of Eastern Ontario Research Institute (CHEO)

Nasana Vaidya

University of Ottawa - Children's Hospital of Eastern Ontario Research Institute (CHEO)

Victoria Heather Gilchrist

University of Ottawa - Children's Hospital of Eastern Ontario Research Institute (CHEO)

Wencheng Li

Rutgers, The State University of New Jersey

Christos Gkogkas

University of Edinburgh - Centre for Discovery Brain Sciences

Maritza Jaramillo

Institut national de la recherche scientifique (INRS) - INRS–Institut Armand-Frappier Research Centre

Seyed Mehdi Jafarnejad

Queen's University Belfast - Centre for Cancer Research and Cell Biology

Tommy Alain

University of Ottawa - Children's Hospital of Eastern Ontario Research Institute (CHEO)

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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 including Inpp5e, encoding an inositol 5-phosphatase that modifies lipid second messenger signalling. We found that viral infection induced 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: oncolytic virus, ribosome profiling, translation, uORF, INPP5E, RNA variant, isoform switch, alternative splicing, Breast cancer

Suggested Citation

Hoang, Huy-Dung and Graber, Tyson Ernst and Jia, Jian-Jun and Vaidya, Nasana and Gilchrist, Victoria Heather and Li, Wencheng and Gkogkas, Christos and Jaramillo, Maritza and Jafarnejad, Seyed Mehdi and Alain, Tommy, Induction of an Alternative 5’ Leader Enhances Translation of Inpp5e and Resistance to Oncolytic Virus Infection (July 16, 2019). Available at SSRN: https://ssrn.com/abstract=3420832 or http://dx.doi.org/10.2139/ssrn.3420832
This version of the paper has not been formally peer reviewed.

Huy-Dung Hoang

University of Ottawa - Children's Hospital of Eastern Ontario Research Institute (CHEO) ( email )

401 Smyth Road
Ottawa, Ontario K1H 8L1
Canada

Tyson Ernst Graber

University of Ottawa - Children's Hospital of Eastern Ontario Research Institute (CHEO) ( email )

401 Smyth Road
Ottawa, Ontario K1H 8L1
Canada

Jian-Jun Jia

University of Ottawa - Children's Hospital of Eastern Ontario Research Institute (CHEO) ( email )

401 Smyth Road
Ottawa, Ontario K1H 8L1
Canada

Nasana Vaidya

University of Ottawa - Children's Hospital of Eastern Ontario Research Institute (CHEO) ( email )

401 Smyth Road
Ottawa, Ontario K1H 8L1
Canada

Victoria Heather Gilchrist

University of Ottawa - Children's Hospital of Eastern Ontario Research Institute (CHEO) ( email )

401 Smyth Road
Ottawa, Ontario K1H 8L1
Canada

Wencheng Li

Rutgers, The State University of New Jersey ( email )

311 North 5th Street
New Brunswick, NJ 08854
United States

Christos Gkogkas

University of Edinburgh - Centre for Discovery Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

Maritza Jaramillo

Institut national de la recherche scientifique (INRS) - INRS–Institut Armand-Frappier Research Centre ( email )

531, boulevard des Prairies
Laval, Québec H7V 1B7
Canada

Seyed Mehdi Jafarnejad

Queen's University Belfast - Centre for Cancer Research and Cell Biology

Belfast
Ireland

Tommy Alain (Contact Author)

University of Ottawa - Children's Hospital of Eastern Ontario Research Institute (CHEO) ( email )

401 Smyth Road
Ottawa, Ontario K1H 8L1
Canada

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