Figure 1.

Schematic illustration of the sequential events taking place in normal translation termination and aberrant translation termination resulting in the activation of nonsense-mediated mRNA decay (NMD). (A) The presence of a termination codon (TC) in the A site of the ribosome provides the signal for translation termination that is marked by recognition of the TC by eukaryotic release factor (eRF)1 and eRF3, a conformational change of eRF1 that facilitates hydrolysis of the terminal peptidyl-transfer RNA (tRNA) bond and the release of the nascent peptide. Subsequently, release of the ribosome from the messenger RNA (mRNA) is facilitated by ABCE1. (B) When translation termination occurs in an unfavorable environment, UPF1 is activated by UPF2 and/or UPF3 that are free in the cytoplasm or positioned nearby on an exon junction complex (EJC). UPF1 activation involves its phosphorylation by SMG1, whose kinase activity is controlled by SMG8 and SMG9. The fate of the stalled ribosomes in the context of NMD activation remains unclear. Phosphorylated UPF1 (indicated by red dots) recruits the NMD-specific SMG6 endonuclease, which cleaves the targeted mRNA nearby the TC and the SMG5/SMG7 heterodimer that stimulates the exonucleolytic degradation of the mRNA by recruiting the CCR4/NOT complex. For clarity, a part of the NMD-activating complex (SMG1, UPF2, and UPF3) is depicted in gray to highlight the factors triggering mRNA degradation in the lower part of the panel.