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HBV ensures optimal replication by encoding X, a multifunctional protein responsible for degrading the structural maintenance of chromosomes (Smc) 5\/6 complex, an anti-HBV factor in hepatocytes. Previous studies suggest that degradation of the Smc5\/6 complex is conserved among viruses from the genus Orthohepadnavirus. Recently, a novel hepadnavirus in cats, domestic cat HBV (DCHBV), has been identified as genetically close to HBV. However, it remains unclear whether the DCHBV X protein possesses similar Smc5\/6 complex-degrading properties. Here, we investigated the degradation of the Smc5\/6 complex by X proteins from viruses of the genus Orthohepadnavirus, including DCHBV, in cells derived from primates and cats. We found that the DCHBV X protein degraded the Smc5\/6 complex in the cells of several host species, and the degree of its anti-Smc5\/6 complex activity differed depending on the host species. Furthermore, 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 for Smc6 of mammalian hepatitis B virus X proteins.<\/jats:p>","DOI":"10.3390\/ijms26146786","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T15:01:05Z","timestamp":1752591665000},"page":"6786","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Conserved Yet Divergent Smc5\/6 Complex Degradation by Mammalian Hepatitis B Virus X Proteins"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3577-9718","authenticated-orcid":false,"given":"Maya","family":"Shofa","sequence":"first","affiliation":[{"name":"Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki, Miyazaki 889-2192, Japan"},{"name":"Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Miyazaki 889-1692, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuri V","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki, Miyazaki 889-2192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2792-4399","authenticated-orcid":false,"given":"Akatsuki","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki, Miyazaki 889-2192, Japan"},{"name":"Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Miyazaki 889-1692, Japan"},{"name":"Center for Animal Disease Control, University of Miyazaki, Miyazaki, Miyazaki 889-2192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Nguyen, M.H., Wong, G., Gane, E., Kao, J.-H., and Dusheiko, G. 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