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IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2018-03-15 , DOI: 10.1093/nar/gky191
Renata C Fleith 1, 2, 3 , Harriet V Mears 1 , Xin Yun Leong 1 , Thomas J Sanford 1 , Edward Emmott 1 , Stephen C Graham 1 , Daniel S Mansur 2 , Trevor R Sweeney 1
Affiliation  

Interferon-induced proteins with tetratricopeptide repeats (IFITs) are highly expressed during the cell-intrinsic immune response to viral infection. IFIT1 inhibits translation by binding directly to the 5′ end of foreign RNAs, particularly those with non-self cap structures, precluding the recruitment of the cap-binding eukaryotic translation initiation factor 4F and ribosome recruitment. The presence of IFIT1 imposes a requirement on viruses that replicate in the cytoplasm to maintain mechanisms to avoid its restrictive effects. Interaction of different IFIT family members is well described, but little is known of the molecular basis of IFIT association or its impact on function. Here, we reconstituted different complexes of IFIT1, IFIT2 and IFIT3 in vitro, which enabled us to reveal critical aspects of IFIT complex assembly. IFIT1 and IFIT3 interact via a YxxxL motif present in the C-terminus of each protein. IFIT2 and IFIT3 homodimers dissociate to form a more stable heterodimer that also associates with IFIT1. We show for the first time that IFIT3 stabilizes IFIT1 protein expression, promotes IFIT1 binding to a cap0 Zika virus reporter mRNA and enhances IFIT1 translation inhibition. This work reveals molecular aspects of IFIT interaction and provides an important missing link between IFIT assembly and function.

中文翻译:


IFIT3 和 IFIT2/3 通过增强与非自身 RNA 的结合来促进 IFIT1 介导的翻译抑制



干扰素诱导的四肽重复蛋白 (IFIT) 在针对病毒感染的细胞内在免疫反应过程中高度表达。 IFIT1 通过直接结合外源 RNA(尤其是具有非自帽结构的 RNA)的 5' 端来抑制翻译,从而阻止帽结合真核翻译起始因子 4F 的募集和核糖体募集。 IFIT1 的存在对在细胞质中复制的病毒提出了要求,以维持避免其限制性影响的机制。不同 IFIT 家族成员之间的相互作用已得到充分描述,但对 IFIT 关联的分子基础或其对功能的影响知之甚少。在这里,我们在体外重建了 IFIT1、IFIT2 和 IFIT3 的不同复合物,这使我们能够揭示 IFIT 复合物组装的关键方面。 IFIT1 和 IFIT3 通过存在于每种蛋白质 C 末端的 YxxxL 基序相互作用。 IFIT2 和 IFIT3 同二聚体解离形成更稳定的异二聚体,该异二聚体也与 IFIT1 结合。我们首次证明 IFIT3 可以稳定 IFIT1 蛋白表达,促进 IFIT1 与 cap0 寨卡病毒报告基因 mRNA 结合,并增强 IFIT1 翻译抑制。这项工作揭示了 IFIT 相互作用的分子方面,并提供了 IFIT 组装和功能之间重要的缺失环节。
更新日期:2018-03-15
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