National Center for Biodefense and Infectious Diseases, Department of Molecular and Microbiology, George Mason University, Manassas, Virginia 20110, USA.
J Biol Chem. 2010 Oct 15;285(42):31930-43. doi: 10.1074/jbc.M110.101709. Epub 2010 Jun 28.
MicroRNAs (miRNAs) are a class of small RNA molecules that function to control gene expression and restrict viral replication in host cells. The production of miRNAs is believed to be dependent upon the DICER enzyme. Available evidence suggests that in T lymphocytes, HIV-1 can both suppress and co-opt the host's miRNA pathway for its own benefit. In this study, we examined the state of miRNA production in monocytes and macrophages as well as the consequences of viral infection upon the production of miRNA. Monocytes in general express low amounts of miRNA-related proteins, and DICER in particular could not be detected until after monocytes were differentiated into macrophages. In the case where HIV-1 was present prior to differentiation, the expression of DICER was suppressed. MicroRNA chip results for RNA isolated from transfected and treated cells indicated that a drop in miRNA production coincided with DICER protein suppression in macrophages. We found that the expression of DICER in monocytes is restricted by miR-106a, but HIV-1 suppressed DICER expression via the viral gene Vpr. Additionally, analysis of miRNA expression in monocytes and macrophages revealed evidence that some miRNAs can be processed by both DICER and PIWIL4. Results presented here have implications for both the pathology of viral infections in macrophages and the biogenesis of miRNAs. First, HIV-1 suppresses the expression and function of DICER in macrophages via a previously unknown mechanism. Second, the presence of miRNAs in monocytes lacking DICER indicates that some miRNAs can be generated by proteins other than DICER.
微小 RNA（miRNA）是一类小 RNA 分子，其功能是在宿主细胞中控制基因表达并限制病毒复制。miRNA 的产生被认为依赖于 DICER 酶。现有证据表明，在 T 淋巴细胞中，HIV-1 既能抑制又能利用宿主的 miRNA 途径为自身谋利。在这项研究中，我们研究了单核细胞和巨噬细胞中 miRNA 产生的状态，以及病毒感染对 miRNA 产生的影响。单核细胞通常表达低水平的 miRNA 相关蛋白，直到单核细胞分化为巨噬细胞后，才能检测到 DICER。如果 HIV-1 先于分化存在，DICER 的表达就会受到抑制。从转染和处理细胞中分离的 RNA 的 miRNA 芯片结果表明，miRNA 产量的下降与巨噬细胞中 DICER 蛋白抑制同时发生。我们发现，miR-106a 限制了单核细胞中 DICER 的表达，但 HIV-1 通过病毒基因 Vpr 抑制 DICER 的表达。此外，对单核细胞和巨噬细胞中 miRNA 表达的分析表明，一些 miRNA 可以由 DICER 和 PIWIL4 共同加工。这里提出的结果对巨噬细胞中病毒感染的病理学和 miRNA 的生物发生都有影响。首先，HIV-1 通过一种未知的机制抑制了巨噬细胞中 DICER 的表达和功能。其次，在缺乏 DICER 的单核细胞中存在 miRNA 表明，一些 miRNA 可以由 DICER 以外的蛋白质产生。
