Inhibition of hepatitis B virus replication by MyD88 involves accelerated degradation of pregenomic RNA and nuclear retention of preS/S RNAs.
Li J, Lin S, Chen Q, Peng L, Zhai J, Liu Y, Yuan Z.
Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China; Research Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China; Institutes of Medical Microbiology and Biomedical Sciences, Fudan University, Shanghai, China.
Abstract
Myeloid differentiation primary response protein (MyD88), which can be induced by interferon-alpha (IFN-alpha), has an antiviral activity against the hepatitis B virus (HBV). The mechanism of this antiviral activity remains poorly understood. Here, we report that MyD88 inhibited HBV replication in HepG2.2.15 cells and in a mouse model. Knock-down of MyD88 expression weakened IFN-alpha-induced inhibition of HBV replication. Furthermore, MyD88 posttranscriptionally reduced the levels of viral RNA. Remarkably, MyD88 accelerated the decay of viral pregenomic RNA in the cytoplasm. Mapping analysis showed that the RNA sequence located in the 5'-proximal region of the pregenomic RNA was critical for the decay. In addition, MyD88 inhibited the nuclear export of preS/S RNAs via the posttranscriptional regulatory element (PRE). The retained preS/S RNAs were shown to degrade in the nucleus. Finally, we found that MyD88 inhibited the expression of polypyrimidine tract-binding protein (PTB), a key nuclear export factor for PRE-containing RNA. Taken together, our results define a novel antiviral mechanism mediated by MyD88 against HBV.