Viral subversion of nonsense-mediated mRNA decay

Figures

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  FIGURE 1.. NMD overview. NMD involves three distinct processes. In the first, NMD substrates are detected by the NMD machinery. In the case of 3′UTR EJC-mediated NMD, if translation terminates, for example, at a premature termination codon (PTC), more than ∼50–55-nt upstream of an exon–exon junction (depicted as “^”), then termination is detected as aberrant. This is because a proteinaceous exon-junction complex (EJC), situated ∼20–24-nt upstream of the exon–exon junction, lies too far downstream from the PTC to be removed by the terminating ribosome. At the EJC, UPF2, anchored by UPF3X (also called UPF3B), interacts with UPF1 and SMG1 at the site of termination. Alternatively, on substrates with unusually long 3′UTRs, a large amount of UPF1 can promiscuously bind to the 3′UTR. The second phase of NMD is the commitment phase, where UPF1 is phosphorylated by its associated kinase, SMG1. This occurs efficiently during a series of regulated events on 3′UTR EJC-mediated NMD and less efficiently on 3′UTR EJC-independent NMD substrates. UPF1 phosphorylation represents a commitment to NMD. During the third phase of NMD, that is, mRNA degradation, phosphorylated UPF1 recruits RNA degradation…

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  FIGURE 2.. Cis- and trans-strategies for NMD avoidance. Both plant and animal viruses adopt either cis-based (left) or trans-based (right) strategies for antagonizing NMD. Cis-based strategies generally involve elements encoded in viral transcripts that may recruit host-cell factors or promote other processes during viral reproduction to shield viral RNA from NMD. Alternatively, trans-based strategies generally involve virally encoded proteins that are produced to directly interfere with host-cell NMD function.

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  FIGURE 3.. Mouse hepatitis virus (MHV) genomic and subgenomic RNA organization. MHV and other coronaviruses, including SARS-CoV-2, produce a genomic transcript that serves as a protein-producing template with an extremely long 3′UTR. A ribosomal frameshifting element within this transcript gives rise to a fusion product with the 5′-most ORF. During the viral life cycle, additional subgenomic RNAs are produced, some of which likewise bear what is presumably a long 3′UTR since only the 5′-most ORF is assumed to be translated. The same leader sequence is present on all genomic and subgenomic RNAs and is attached by a unique template-switching mechanism.