RNA Biology Research Laboratory, Molecular and Human Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India.
EMBO Rep. 2013 Nov;14(11):1008-16. doi: 10.1038/embor.2013.149. Epub 2013 Sep 13.
In mammalian macrophages, the expression of a number of cytokines is regulated by miRNAs. Upon macrophage activation, proinflammatory cytokine mRNAs are translated, although the expression of miRNAs targeting these mRNAs remains largely unaltered. We show that there is a transient reversal of miRNA-mediated repression during the early phase of the inflammatory response in macrophages, which leads to the protection of cytokine mRNAs from miRNA-mediated repression. This derepression occurs through Ago2 phosphorylation, which results in its impaired binding to miRNAs and to the corresponding target mRNAs. Macrophages expressing a mutant, non-phosphorylatable AGO2--which remains bound to miRNAs during macrophage activation--have a weakened inflammatory response and fail to prevent parasite invasion. These findings highlight the relevance of the transient relief of miRNA repression for macrophage function.
在哺乳动物巨噬细胞中，许多细胞因子的表达受 miRNA 调控。在巨噬细胞激活时，促炎细胞因子的 mRNA 被翻译，尽管针对这些 mRNA 的 miRNA 的表达仍基本不变。我们表明，在巨噬细胞炎症反应的早期阶段，存在 miRNA 介导的抑制的短暂逆转，这导致细胞因子 mRNA 免受 miRNA 介导的抑制。这种去抑制作用是通过 Ago2 磷酸化发生的，这导致其与 miRNA 和相应的靶 mRNA 的结合受损。表达突变型、不可磷酸化的 Ago2 的巨噬细胞（在巨噬细胞激活期间仍与 miRNA 结合）的炎症反应减弱，无法阻止寄生虫入侵。这些发现强调了 miRNA 抑制的短暂缓解对巨噬细胞功能的相关性。
