Conserved yet Divergent Smc5/6 Complex Degradation by Mammalian Hepatitis B Virus X Proteins

Abstract

Hepatitis B virus (HBV), belonging to the genus Orthohepadnavirus, can cause chronic hepatitis and hepatocarcinoma in humans. HBV ensures optimal replication by encoding X, a multifunctional protein responsible for degrading the structural maintenance of the chromosome (Smc) 5/6 complex, an anti-HBV factor in hepatocytes. Previous studies suggest that the degradation activity of the Smc5/6 complex is conserved among viruses from the genus Orthohepadnavirus. Recently, a novel hepadnavirus in cats, domestic cat hepadnavirus (DCH) or DCH B virus (DCHBV), has been identified to be genetically close to HBV. However, it remains unclear whether the DCHBV X protein possesses a similar Smc5/6 complex-degrading activity. Here, we investigated the degradation activity of the Smc5/6 complex by X of the viruses of the genus Orthohepadnavirus, including DCHBV, in cells derived from primates and cats. We found that the DCHBV X protein degraded Smc6 in the cells of several host species, and the degree of its anti-Smc5/6 activity differed depending on the host species. Furthermore, we demonstrated that the DCHBV X protein degraded Smc6 independently of DNA-binding protein 1 (DDB1), which is a critical host factor for HBV X-mediated Smc6 degradation. Our findings highlight the conserved yet divergent degradation machinery of the Smc5/6 complex of mammalian hepatitis B virus X proteins. ImportanceHepatitis B virus (HBV) causes chronic hepatitis and liver cancer in humans. HBV mainly acts by degrading the Smc5/6 complex, a defense mechanism in liver cells that restricts viral replication. Smc5/6 degradation, mediated by the HBV protein X, is conserved across the viruses in the same genus. However, it remains unclear whether the novel domestic cat HBV (DCHBV) exhibits similar capabilities. Here, we compared Smc5/6 degradation by the X proteins of various HBVs, including DCHBV, in different primate and feline cells. The DCHBV X protein could degrade Smc6 in various host cells at different levels. Notably, DCHBV X could degrade Smc6 without requiring DDB1, a host factor essential for HBV X-mediated Smc6 degradation. These findings highlight the conserved yet distinct strategies employed by mammalian HBVs to evade the host Smc5/6 system, expanding our understanding of viral adaptation and persistence across species.