Osteopetrosis-Associated Transmembrane Protein 1 Recruits RNA Exosome To Restrict Hepatitis B Virus Replication.

Hepatitis B virus (HBV) chronically infects approximately 350 million people worldwide, and 600,000 deaths are caused by HBV-related hepatic failure, liver cirrhosis, and hepatocellular carcinoma annually. It is important to reveal the mechanism underlying the regulation of HBV replication. This study demonstrated that the osteopetrosis-associated transmembrane protein 1 (Ostm1) plays an inhibitory role in HBV replication. Ostm1 represses the levels of HBeAg and HBsAg proteins, HBV 3.5-kb and 2.4/2.1-kb RNAs, and core-associated DNA in HepG2, Huh7, and NTCP-HepG2 cells. Notably, Ostm1 has no direct effect on the activity of HBV promoters or the transcription of HBV RNAs, instead, Ostm1 binds to HBV RNA to facilitate the RNA decay. Detailed studies further demonstrated that Ostm1 binds to and recruits RNA exosome complex to promote the degradation of HBV RNAs, and knock-down of RNA exosome component exonuclease 3 (Exosc3) leads to the elimination of Ostm1-mediated repression of HBV replication. Mutant analyses revealed that N-terminal domain, the transmembrane domain, and C-terminal domain are responsible for the repression of HBV replication and C-terminal domain is required for the interaction with RNA exosome complex. Moreover, Ostm1 production is not regulated by interferon-alpha (IFN-alpha) or IFN-gamma, and the expression of INF signaling components is not affected by Ostm1, suggesting that Ostm1 anti-HBV activity is independent on IFN signaling pathway. In conclusion, this study revealed a distinct mechanism underlying the repression of HBV replication, in which Ostm1 binds to HBV RNA and recruits RNA exosome to degrade the viral RNA, thereby restricting HBV replication.Importance Hepatitis B virus (HBV) is a human pathogen infecting liver to cause a variety of diseases ranging from acute hepatitis to advanced liver diseases, fulminate hepatitis, liver cirrhosis, and hepatocellular carcinoma, thereby causing a major health problem worldwide. In this study, the authors demonstrated that Ostm1 plays an inhibitory role in HBV proteins production, RNA expression, and DNA replication. However, Ostm1 has no effect on the activities of the four HBV promoters; instead, it binds to HBV RNA and recruits RNA exosome to promote HBV RNA degradation. The authors further demonstrated that anti-HBV activity of Ostm1 is independent on interferon signaling pathway. In conclusion, this study revealed a distinct mechanism underlying the repression of HBV replication, and suggested that Ostm1 is a potential therapeutic agent for HBV infection.