Jing Qing, Huang Shuang, Guth Sabine, Zarubin Tyler, Motoyama Andrea, Chen Jianming, Di Padova Franco, Lin Sheng-Cai, Gram Hermann, Han Jiahuai
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell. 2005 Mar 11;120(5):623-34. doi: 10.1016/j.cell.2004.12.038.
AU-rich elements (AREs) in the 3' untranslated region (UTR) of unstable mRNAs dictate their degradation. An RNAi-based screen performed in Drosophila S2 cells has revealed that Dicer1, Argonaute1 (Ago1) and Ago2, components involved in microRNA (miRNA) processing and function, are required for the rapid decay of mRNA containing AREs of tumor necrosis factor-alpha. The requirement for Dicer in the instability of ARE-containing mRNA (ARE-RNA) was confirmed in HeLa cells. We further observed that miR16, a human miRNA containing an UAAAUAUU sequence that is complementary to the ARE sequence, is required for ARE-RNA turnover. The role of miR16 in ARE-RNA decay is sequence-specific and requires the ARE binding protein tristetraprolin (TTP). TTP does not directly bind to miR16 but interacts through association with Ago/eiF2C family members to complex with miR16 and assists in the targeting of ARE. miRNA targeting of ARE, therefore, appears to be an essential step in ARE-mediated mRNA degradation.
不稳定mRNA的3'非翻译区（UTR）中的富含AU元件（ARE）决定了它们的降解。在果蝇S2细胞中进行的基于RNA干扰的筛选表明，参与微小RNA（miRNA）加工和功能的组分Dicer1、AGO1和AGO2是含有肿瘤坏死因子-α的ARE的mRNA快速降解所必需的。在HeLa细胞中证实了Dicer在含ARE的mRNA（ARE-RNA）不稳定性中的需求。我们进一步观察到，miR16是一种含有与ARE序列互补的UAAAUAUU序列的人类miRNA，它是ARE-RNA周转所必需的。miR16在ARE-RNA降解中的作用是序列特异性的，并且需要ARE结合蛋白三磷酸四脯氨酸（TTP）。TTP不直接与miR16结合，而是通过与AGO/eiF2C家族成员结合来与miR16形成复合物，并协助靶向ARE。因此，miRNA对ARE的靶向似乎是ARE介导的mRNA降解中的一个关键步骤。
