7 pag.; 3 figs. Nonsense-mediated mRNA decay (NMD) is a pathway that detects and degrades mRNAs containing premature translation termination codons (PTCs). In humans, recognition of these aberrant mRNAs requires an exon-junction-complex (EJC) placed downstream of a PTC and the dynamic interaction of several UPF/SMG proteins, the ribosome and the EJC. These interactions promote UPF1 phosphorylation by SMG1 kinase, triggering mRNA degradation. Recent progress in our understanding of NMD has been achieved by combining cryo-electron microscopy, high-resolution structures, interaction data and functional assays. These studies uncovered a mechanism regulating SMG1 kinase as well as the architecture and functional implications of a complex containing UPF1, UPF2, UPF3 and EJC. Collectively these findings reveal the role of protein scaffolds and conformational changes in NMD regulation. This work was funded by the Spanish Government (SAF2011-22988 to O.L.), the ‘Red Tematica de Investigacion Cooperativa en Cancer(RTICC)’ (RD06/0020/1001 to O.L.) and the Human Frontiers Science Program (RGP39/2008 to O.L.). O.L. acknowledges also support by the‘Ramon Areces’ Foundation. Peer reviewed