title: miR-146a and miR-370 coordinate enterovirus 71-induced cell apoptosis through targeting SOS1 and GADD45β.
abstract: Enterovirus 71 (EV71) is an emerging life-threatening pathogen particularly in the Asia-Pacific region. The major pathogenic feature in EV71-infected cells is apoptosis. However, which molecular mechanism mainly contributes to EV71-induced apoptosis is not investigated thoroughly. MicroRNAs (MiRNAs), the newly discovered molecules, govern a wide range of biological functions through post-transcriptional regulation including viral pathogenesis. Whether miRNAs and messenger RNAs (mRNAs) coordinate to trigger host cell apoptosis in EV71 infection was investigated in this study. We conducted an apoptosis-oriented approach using both mRNA and miRNA profiling and bioinformatic analysis. We identified two major apoptosis-associated signalling pathways, Bcl2 antagonist of cell death (BAD) phosphorylation and p53-dependent apoptosis pathways, in which Son of sevenless homolog 1 (SOS1) and Growth arrest and DNA damage-inducible protein 45β (GADD45β) were predicted as targets of miR-146a and miR-370 respectively. Luciferase reporter assays and Western blots demonstrated the negative regulation between miR-146a and SOS1 and between miR-370 and GADD45β. Silencing of miR-146a restored SOS1 expression and partially attenuated EV71 infection-induced apoptosis. Conversely, ectopic expression of miR-370 decreased virus infection-induced GADD45β expression and also diminished apoptosis. Finally, the transfection of antagomiR-146a and miR-370 contributed to attenuating EV71 infection-induced apoptosis. Herein we clearly demonstrate that EV71-induced cell apoptosis is partly governed by altered miRNAs.
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.|NTU Center for Genomic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Bing-Ching
authors.initials: BC
authors.lastname: Ho
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Singh
authors.initials: S
authors.lastname: Sher
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.|NTU Center for Genomic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Center for Optoelectronic Biomedicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Sung-Liang
authors.initials: SL
authors.lastname: Yu
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|NTU Center for Genomic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000943:Antigens, Differentiation / Q000378:metabolism*; D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D019295:Computational Biology; D029821:Enterovirus A, Human / Q000502:physiology*; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D054884:Host-Pathogen Interactions; D006801:Humans; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D035683:MicroRNAs / Q000378:metabolism*; D020837:SOS1 Protein / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D008156:Luciferases; D035683:MicroRNAs; D020837:SOS1 Protein; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C542542:MIRN146 microRNA, human; C526503:MIRN370 microRNA, human