No-nonsense: insights into the functional interplay of nonsense-mediated mRNA decay factors

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.

Automated summary

Nonsense-mediated messenger RNA decay (NMD) is an important mRNA degradation pathway in eukaryotic cells, controlling mRNA quality and abundance, as well as degrading viral RNA. NMD recognizes mRNAs with premature termination codons (PTCs) and targets them for degradation through a branched network of interconnected pathways. The structural understanding and functional interplay of mammalian NMD factors, such as UPF1, UPF3B, and UPF3A, play crucial roles in NMD pathway choice and regulation. The context-dependent nature of mammalian NMD, determined by developmental stage, tissue, and cell types, further highlights the complexity of gene regulation in this pathway.