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

被引:60
作者
Fu, Ya-Ru [1 ]
Liu, Xi-Juan [1 ]
Li, Xiao-Jun [1 ]
Shen, Zhang-zhou [1 ]
Yang, Bo [1 ]
Wu, Cong-Cong [1 ]
Li, Jia-Fu [2 ]
Miao, Ling-Feng [1 ]
Ye, Han-Qing [1 ]
Qiao, Guan-Hua [1 ]
Rayner, Simon [1 ]
Chavanas, Stephane [3 ]
Davrinche, Christian [3 ]
Britt, William J. [4 ]
Tang, Qiyi [5 ]
McVoy, Michael [6 ]
Mocarski, Edward [7 ]
Luo, Min-Hua [1 ]
机构
[1] Chinese Acad Sci, Wuhan Inst Virol, State Key Lab Virol, Wuhan, Peoples R China
[2] Wuhan Univ, Zhongnan Hosp, Wuhan 430072, Peoples R China
[3] Fac Med Toulouse, INSERM, U563, F-31073 Toulouse, France
[4] Univ Alabama Birmingham, Sch Med, Dept Pediat, Birmingham, AL USA
[5] Ponce Sch Med & Hlth Sci, Dept Microbiol, Ponce, PR USA
[6] Virginia Commonwealth Univ, Sch Med, Dept Pediat, Richmond, VA USA
[7] Emory Univ, Sch Med, Atlanta, GA USA
基金
中国国家自然科学基金;
关键词
HEPATITIS-B-VIRUS; GENE-EXPRESSION; HEPATOCELLULAR-CARCINOMA; PROGENITOR CELLS; HEARING-LOSS; INFECTION; CYCLE; PROTEIN; DYSREGULATION; INHIBITION;
D O I
10.1128/JVI.01740-14
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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-1E1, 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. This suggests a role for miR-21 downregulation in the neuropathogenesis of HCMV infection of the developing CNS. IMPORTANCE Human cytomegalovirus (HCMV) is a ubiquitous pathogen and has very high prevalence among population, especially in China, and congenital HCMV infection is a major cause for birth defects. Elucidating virus-host interactions that govern HCMV replication in neuronal cells is critical to understanding the neuropathogenesis of birth defects resulting from congenital infection. In this study, we confirm that HCMV infection downregulates miR-21 but upregulates Cdc25a. Further determined the negative effects of cellular miRNA miR-21 on HCMV replication in neural progenitor/stem cells and U-251MG glioblastoma/astrocytoma cells. More importantly, our results provide the first evidence that miR-21 negatively regulates HCMV replication by targeting Cdc25a, a vital cell cycle regulator. We further found that viral gene products of IE1, pp71, and UL26 play roles in inhibiting miR-21 expression, which in turn causes increases in Cdc25a and benefits HCMV replication. Thus, miR-21 appears to be an intrinsic antiviral factor that represents a potential target for therapeutic intervention.
引用
收藏
页码:1070 / 1082
页数:13
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