Ding Lei, Spencer Andrew, Morita Kiyokazu, Han Min
Howard Hughes Medical Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, 80309, USA.
Mol Cell. 2005 Aug 19;19(4):437-47. doi: 10.1016/j.molcel.2005.07.013.
In metazoans, microRNAs (miRNAs) carry out various regulatory functions through association with multiprotein miRNA-induced silencing complexes (miRISCs) that contain Dicer and Argonaute proteins. How miRNAs regulate the expression of their mRNA targets remains a major research question. We have identified the C. elegans ain-1 gene through a genetic suppressor screen and shown that it functions with the heterochronic genetic pathway that regulates developmental timing. Biochemical analysis indicates that AIN-1 interacts with protein complexes containing an Argonaute protein, Dicer, and miRNAs. AIN-1 shares homology with the candidate human neurological disease protein GW182, shown to localize in cytoplasmic processing bodies that are sites of mRNA degradation and storage. A functional AIN-1::GFP also localizes at the likely worm processing bodies. When coexpressed from transgenes, AIN-1 targets ALG-1 to the foci. These results suggest a model where AIN-1 regulates a subset of miRISCs by localization to the processing bodies, facilitating degradation or translational inhibition of mRNA targets.
在多细胞动物中，微小RNA（miRNA）通过与包含Dicer和Argonaute蛋白的多蛋白微小RNA诱导沉默复合体（miRISC）结合来执行各种调节功能。miRNA如何调节其mRNA靶标的表达仍然是一个主要的研究问题。我们通过遗传抑制筛选鉴定了秀丽隐杆线虫的ain-1基因，并表明它与调节发育时间的异时性遗传途径一起发挥作用。生化分析表明，AIN-1与包含Argonaute蛋白、Dicer和miRNA的蛋白复合体相互作用。AIN-1与候选人类神经疾病蛋白GW182具有同源性，GW182定位于细胞质加工小体，而细胞质加工小体是mRNA降解和储存的场所。功能性AIN-1::GFP也定位于可能的线虫加工小体。当从转基因中共表达时，AIN-1将ALG-1靶向到这些位点。这些结果提示了一种模型，即AIN-1通过定位于加工小体来调节一部分miRISC，促进mRNA靶标的降解或翻译抑制。
