Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways
Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways
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DOI：
10.1038/emboj.2008.17
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发表时间：
2008-03-05
期刊：
影响因子：
11.4
通讯作者：
Kulozik, Andreas E.
中科院分区：
文献类型：
--
作者：
Ivanov, Pavel V.;Gehring, Niels H.;Kulozik, Andreas E.
无义介导的mRNA衰变（NMD）代表控制野生型和异常mRNA表达的关键机制。蛋白质UPF1在翻译终止的背景下的磷酸化有助于将mRNA提交给NMD。我们报告说，翻译终止抑制UPF1和刺激细胞质聚（A）结合蛋白（PABPC1）。UPF1在GTP和GDP结合状态下均与eRF1和eRF3的GTP结合域结合。重要的是，突变研究表明UPF1可以通过UPF2或UPF3b与外显子连接复合物（EJC）相互作用，使其磷酸化并激活NMD。在此基础上，我们讨论了一个综合模型，其中UPF1停止翻译终止和磷酸化SMG1，如果终止促进PABPC 1与eRF3的相互作用不能容易地发生。EJC与UPF2或UPF3b作为辅因子，通过UPF1干扰生理终止。该模型集成了以前竞争的NMD模型，并提出了替代NMD途径的机制基础。
Nonsense-mediated mRNA decay (NMD) represents a key mechanism to control the expression of wild-type and aberrant mRNAs. Phosphorylation of the protein UPF1 in the context of translation termination contributes to committing mRNAs to NMD. We report that translation termination is inhibited by UPF1 and stimulated by cytoplasmic poly(A)-binding protein (PABPC1). UPF1 binds to eRF1 and to the GTPase domain of eRF3 both in its GTP- and GDP-bound states. Importantly, mutation studies show that UPF1 can interact with the exon junction complex (EJC) alternatively through either UPF2 or UPF3b to become phosphorylated and to activate NMD. On this basis, we discuss an integrated model where UPF1 halts translation termination and is phosphorylated by SMG1 if the termination-promoting interaction of PABPC1 with eRF3 cannot readily occur. The EJC, with UPF2 or UPF3b as a cofactor, interferes with physiological termination through UPF1. This model integrates previously competing models of NMD and suggests a mechanistic basis for alternative NMD pathways.