微RNA（miRNAs）对基因表达具有广泛的调节作用，故其在细胞内被精确调控。Ago2是miRNA途径中的一个最重要的效应蛋白。在前期工作中，我们鉴定了Ago2的乙酰化修饰及其位点，并发现Ago2乙酰化可以影响miRNA途径介导的基因沉默效应的活性。本项目将深入阐明Ago2乙酰化调控miRNA途径活性的新分子机制：即Ago2乙酰化可影响其直接招募一些前体miRNA (pre-miRNA)形成Ago2-pre-miRNA复合物, 而后者和Dicer/TARBP2结合促进形成装载体miRLC, 最终调控一群特异性miRNA的生成而改变miRNA表达谱。我们还将剖析Ago2乙酰化的生物学功能，包括Ago2乙酰化受何种信号及相关酶激活、Ago2乙酰化位点突变型对肿瘤细胞及移殖瘤生长特性的影响、临床肿瘤样本中Ago2乙酰化程度与肿瘤发生之间的相关性等，阐明Ago2乙酰化调控miRNA途径的生理意义。

MicroRNAs (miRNAs) have broad regulatory roles on gene expression, therefore the miRNA pathway in organisms is precisely controlled. AGO2 is one of the most important regulatory factor in the miRNA pathway, because it is an effector of the miRNA-induced silencing complex (miRISC). In our preliminary work we have identified Ago2 acetylation and its sites, and found Ago2 acetylation can affect the activities of the gene silencing effects mediated by the miRNA pathways. The project will further explore molecular mechanisms of Ago2 acetylation regulating the miRNA pathway activities: Ago2 acetylation may affect the recruitment of some precursor miRNA (pre-miRNA) to form Ago2-pre-miRNA complexes, which can bind to Dicer/TARBP2 to promote the formation of miRLC (miRISC loading complex), thus ultimately influencing the biogenesis of a group of specific miRNAs and changing the miRNA expression profiles. We will also analyze the biological functions of Ago2 acetylation, including the activation of Ago2 acetylation by which signaling pathway and acetyltransferase/deacetyltransferase, the effects of acetylation-site mutant of Ago2 on tumor cell and xenografted tumor growth characteristics, and the correlation between Ago2 acetylation degree and tumorigeneis in clinical tumor samples, to finally clarify the physiological relevance of Ago2 acetylation regulating the miRNA pathways.