Tumor Suppressor p53 Inhibits Hepatitis B Virus Replication by Downregulating HBx via E6AP-Mediated Proteasomal Degradation in Human Hepatocellular Carcinoma Cell Lines

• Published in: Viruses Vol. 14; no. 10; p. 2313
• Main Authors: Lim, Ha-Yeon, Han, Jiwoo, Yoon, Hyunyoung, Jang, Kyung Lib
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.10.2022; MDPI
• Subjects: Amino acids; Antigens; Binding sites; Cell culture; Control; Development and progression; E6-associated protein; Enzymes; Genomes; HBx; Health aspects; Hepatitis B; Hepatitis B virus; Hepatocellular carcinoma; Hepatoma; Infections; Kinases; Liver cancer; p53; p53 Protein; Plasmids; Polyethylene glycol; proteasome; Proteasomes; Proteins; Replication; Tumor cell lines; Tumor proteins; Tumor suppressor genes; Tumorigenesis; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Viral infections; South Korea; United States > US; Germany
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v14102313

HBx, a multifunctional regulatory protein, plays an essential role in the replication and pathogenesis of the hepatitis B virus (HBV). In this study, we found that in human hepatoma cells, the tumor suppressor p53 downregulates HBx via ubiquitin-dependent proteasomal degradation. p53 transcriptional activity that results from HBV infection was not essential for this effect. This was shown by treatment with a potent p53 inhibitor, pifithrin-α. Instead, we found that p53 facilitated the binding of E6-associated protein (E6AP), which is an E3 ligase, to HBx and induced E6AP-mediated HBx ubiquitination in a ternary complex of p53, E6AP, and HBx. The ability of p53 to induce E6AP-mediated downregulation of HBx and inhibit HBV replication was demonstrated in an in vitro HBV infection system. This study may provide insights into the regulation of HBx and HBV replication, especially with respect to p53 status, which may also help in understanding HBV-associated tumorigenesis in patients.