Nonsense-mediated decay (NMD) is a host RNA control pathway that removes aberrant transcripts with long 3’ untranslated regions (UTRs) due to premature termination codons that arise through mutation or defective splicing. To maximize coding potential, RNA viruses often contain internally located stop codons that should also be prime targets for NMD. We have identified multiple strategies used by small RNA viruses to evade NMD. The ribosome readthrough structure just downstream of the TCV p28 termination codon stabilized an NMD-sensitive reporter as did an unstructured segment at the beginning of the 3’ UTR. NMD-resistance was unaffected by conversion of 19 pyrimidines in the 46-nt unstructured segment to purines, but abolished when secondary structure was added to the region without changing the sequence. The TCV genome thus has features that are inherently NMD-resistant and these strategies could be widespread among RNA viruses and NMD-resistant host mRNAs with long 3’ UTRs. The strategy used by a second small RNA virus was also novel. We showed that a protein known to be required for long-distance movement of PEMV2 also protects both viral and host mRNAs from NMD. RNA-seq analyses of the Nicotiana benthamiana transcriptome revealed that PEMV2 infection significantly impairs the host NMD pathway. RNA viruses routinely induce large-scale changes in host gene expression, and, like PEMV2, may use NMD-inhibition to alter the host transcriptome in an effort to increase virus amplification.
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