MicroRNA miR-21 Attenuates Human Cytomegalovirus Replication in Neural Cells by Targeting Cdc25a

作者：Yaru Fu, Xiaojian Liu, Xiaojun Li, Zhang‐Zhou Shen, Bo Yang, Cong-Cong Wu, Jiafu Li, Ling-Feng Miao, Han‐Qing Ye, Guan-Hua Qiao, Simon Rayner, Stéphane Chavanas, Christian Davrinche, William J. Britt, Qiyi Tang, Michael A. McVoy, Edward S. Mocarski, Min‐Hua Luo · 发表于：Journal of Virology · 年份：2014 · DOI：10.1128/jvi.01740-14 · 被引用次数：72 · 研究领域：Cytomegalovirus and herpesvirus research、MicroRNA in disease regulation、Hydrogen's biological and therapeutic effects

UNLABELLED: Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, primarily manifesting as neurological disorders. HCMV infection alters expression of cellular microRNAs (miRs) and induces cell cycle arrest, which in turn modifies the cellular environment to favor virus replication. Previous observations found that HCMV infection reduces miR-21 expression in neural progenitor/stem cells (NPCs). Here, we show that infection of NPCs and U-251MG cells represses miR-21 while increasing the levels of Cdc25a, a cell cycle regulator and known target of miR-21. These opposing responses to infection prompted an investigation of the relationship between miR-21, Cdc25a, and viral replication. Overexpression of miR-21 in NPCs and U-251MG cells inhibited viral gene expression, genome replication, and production of infectious progeny, while shRNA-knockdown of miR-21 in U-251MG cells increased viral gene expression. In contrast, overexpression of Cdc25a in U-251MG cells increased viral gene expression and production of infectious progeny and overcame the inhibitory effects of miR-21 overexpression. Three viral gene products-IE1, pp71, and UL26-were shown to inhibit miR-21 expression at the transcriptional level. These results suggest that Cdc25a promotes HCMV replication and elevation of Cdc25a levels after HCMV infection are due in part to HCMV-mediated repression of miR-21. Thus, miR-21 is an intrinsic antiviral factor that is modulated by HCMV infection. ...