title: Hexokinase 2 controls cellular stress response through localization of an RNA-binding protein.
abstract: Subcellular localization of RNA-binding proteins is a key determinant of their ability to control RNA metabolism and cellular stress response. Using an RNAi-based kinome-wide screen, we identified hexokinase 2 (HK2) as a regulator of the cytoplasmic accumulation of hnRNP A1 in response to hypertonic stress and human rhinovirus infection (HRV). We show that inhibition of HK2 expression or pharmacological inhibition of HK2 activity blocks the cytoplasmic accumulation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), restores expression of B-cell lymphoma-extra large (Bcl-xL), and protects cells against hypertonic stress-induced apoptosis. Reduction of HK2 protein levels by knockdown results in decreased HRV replication, a delay in HRV-induced cell death, and a reduced number of infected cells, all of which can be rescued by forced expression of a cytoplasm-restricted hnRNP A1. Our data elucidate a novel role for HK2 in cellular stress response and viral infection that could be exploited for therapeutic intervention.
authors.affiliation: 1] Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada [2] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Courteau
authors.affiliation: Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Crasto
authors.affiliation: 1] Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada [2] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Hassanzadeh
authors.affiliation: Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada.
authors.forename: S D
authors.initials: SD
authors.lastname: Baird
authors.affiliation: Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Hodgins
authors.affiliation: 1] Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada [2] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: U
authors.initials: U
authors.lastname: Liwak-Muir
authors.affiliation: Department of Pathology and Laboratory Medicine, James Hogg Research Center, University of British Columbia, Vancouver, British Columbia V6Z 1Y6, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Fung
authors.affiliation: Department of Pathology and Laboratory Medicine, James Hogg Research Center, University of British Columbia, Vancouver, British Columbia V6Z 1Y6, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Luo
authors.affiliation: 1] Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada [2] Department of Pediatrics, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: D F
authors.initials: DF
authors.lastname: Stojdl
authors.affiliation: 1] Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada [2] Department of Pediatrics, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: R A
authors.initials: RA
authors.lastname: Screaton
authors.affiliation: 1] Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada [2] Department of Pediatrics, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Holcik
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D004770:Enterovirus / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics* / Q000378:metabolism; D006593:Hexokinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D057054:Molecular Imaging; D009997:Osmotic Pressure; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012229:Rhinovirus / Q000502:physiology*; D015398:Signal Transduction; D014779:Virus Replication; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; D004791:Enzyme Inhibitors; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034741:RNA, Small Interfering; D051020:bcl-X Protein; C000619656:hnRNPA1 protein, human; D006593:Hexokinase