miR-146a and miR-370 coordinate Enterovirus 71-induced cell apoptosis through targeting SOS1 and GADD45β

• Main Authors: Ya-Ling Chang, 張雅玲
• Other Authors: Pan-Chyr Yang
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/50597487412488897203

博士 === 國立臺灣大學 === 分子醫學研究所 === 103 === 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. MiRNAs, the newly discovered molecules, govern a wide range of biological functions through post-transcriptional regulation and play roles in viral pathogenesis. Whether miRNAs and mRNAs coordinate to trigger host cell apoptosis in EV71 infection was investigated in this study. We conducted an apoptosis-oriented approach by using both mRNA and miRNA profiling and bioinformatic analysis. We identified two major apoptosis-associated signaling 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 co-expression of antagomiR-146a and miR-370 contributed to attenuating EV71 infection-induced apoptosis. Herein we clearly demonstrate a new mechanism that EV71-induced cell apoptosis is partly governed by altered miRNAs.