Cell-intrinsic regulation of HBV RNAs by the nonsense-mediated mRNA decay pathway controls viral replication

Hepatitis B virus (HBV) is a causative agent for chronic liver hepatitis, which confers risk for liver cirrhosis and hepatocellular carcinoma. Among key viral transcripts, HBV pregenome RNA (pgRNA) is indispensable for viral replication, and therefore, quality control of pgRNA is critical for the HBV life cycle. Here, we revealed degradation of HBV RNAs by the nonsense-mediated mRNA decay (NMD) pathway, a host surveillance system of RNA quality. Degradation kinetics of the HBV RNAs indicated that pgRNA, 2.4 knt RNA, and 2.1 knt RNA were targets of the NMD pathway and also interacted robustly with phosphorylated UPF1 but not X RNA. Northern blotting showed that decay of the viral NMD candidates was also delayed in NMD-deficient cells. In contrast, NMD depletion promoted the formation of capsids containing genomic DNA and exhibiting antigen production. Our data strongly suggest that the NMD pathway inspects HBV transcripts to regulate HBV replication as an intrinsic antiviral defense.