School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, U.K.
Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, U.K.
Biochem J. 2022 May 13;479(9):973-993. doi: 10.1042/BCJ20210556.
Nonsense-mediated messenger RNA decay (NMD) represents one of the main surveillance pathways used by eukaryotic cells to control the quality and abundance of mRNAs and to degrade viral RNA. NMD recognises mRNAs with a premature termination codon (PTC) and targets them to decay. Markers for a mRNA with a PTC, and thus NMD, are a long a 3'-untranslated region and the presence of an exon-junction complex (EJC) downstream of the stop codon. Here, we review our structural understanding of mammalian NMD factors and their functional interplay leading to a branched network of different interconnected but specialised mRNA decay pathways. We discuss recent insights into the potential impact of EJC composition on NMD pathway choice. We highlight the coexistence and function of different isoforms of up-frameshift protein 1 (UPF1) with an emphasis of their role at the endoplasmic reticulum and during stress, and the role of the paralogs UPF3B and UPF3A, underscoring that gene regulation by mammalian NMD is tightly controlled and context-dependent being conditional on developmental stage, tissue and cell types.
无意义介导的 mRNA 降解 (NMD) 是真核细胞用来控制 mRNA 质量和丰度并降解病毒 RNA 的主要监控途径之一。NMD 识别具有提前终止密码子 (PTC) 的 mRNA，并将其靶向降解。具有 PTC（因此具有 NMD）的 mRNA 的标志物是长的 3'-非翻译区和终止密码子下游的外显子连接复合物 (EJC) 的存在。在这里，我们回顾了我们对哺乳动物 NMD 因子的结构理解及其功能相互作用，这些作用导致了不同相互连接但专业化的 mRNA 降解途径的分支网络。我们讨论了最近对 EJC 组成对 NMD 途径选择的潜在影响的见解。我们强调了移码蛋白 1 (UPF1) 的不同同工型的共存和功能，重点是它们在内质网和应激期间的作用，以及旁系同源物 UPF3B 和 UPF3A 的作用，强调了哺乳动物 NMD 的基因调控受到严格控制且依赖于上下文，取决于发育阶段、组织和细胞类型。
