Interplay between coronavirus, a cytoplasmic RNA virus, and nonsense-mediated mRNA decay pathway

Significance

Coronaviruses (CoVs) are important pathogens for humans and domestic animals. The development of effective countermeasures against CoVs requires an understanding of the host pathways that regulate viral gene expression and the viral subversion mechanisms. However, little is known about how the stability of viral mRNAs is controlled. We show that the nonsense-mediated decay (NMD) pathway, which primarily targets aberrant cellular mRNAs for degradation, also induced the degradation of CoV mRNAs that are of cytoplasmic origin. Our study further suggests the importance of CoV-induced inhibition of the NMD pathway, mediated by a viral protein, for efficient CoV replication. The present study highlights an interplay between the NMD pathway and CoVs that modulates viral replication by controlling the stability of viral mRNAs.

Abstract

Coronaviruses (CoVs), including severe acute respiratory syndrome CoV and Middle East respiratory syndrome CoV, are enveloped RNA viruses that carry a large positive-sense single-stranded RNA genome and cause a variety of diseases in humans and domestic animals. Very little is known about the host pathways that regulate the stability of CoV mRNAs, which carry some unusual features. Nonsense-mediated decay (NMD) is a eukaryotic RNA surveillance pathway that detects mRNAs harboring aberrant features and targets them for degradation. Although CoV mRNAs are of cytoplasmic origin, the presence of several NMD-inducing features (including multiple ORFs with internal termination codons that create a long 3′ untranslated region) in CoV mRNAs led us to explore the interplay between the NMD pathway and CoVs. Our study using murine hepatitis virus as a model CoV showed that CoV mRNAs are recognized by the NMD pathway as a substrate, resulting in their degradation. Furthermore, CoV replication induced the inhibition of the NMD pathway, and N protein (a viral structural protein) had an NMD inhibitory function that protected viral mRNAs from rapid decay. Our data further suggest that the NMD pathway interferes with optimal viral replication by degrading viral mRNAs early in infection, before sufficient accumulation of N protein. Our study presents clear evidence for the biological importance of the NMD pathway in controlling the stability of mRNAs and the efficiency of replication of a cytoplasmic RNA virus.