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

Lim, Ha-Yeon; Han, Jiwoo; Yoon, Hyunyoung; Jang, Kyung Lib

doi:10.3390/v14102313

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

by

Ha-Yeon Lim

^1,†,

Jiwoo Han

^1,†,

Hyunyoung Yoon

¹ and

Kyung Lib Jang

^1,2,3,*

¹

Department of Integrated Biological Science, The Graduate School, Pusan National University, Busan 46241, Korea

²

Department of Microbiology, College of Natural Science, Pusan National University, Busan 46241, Korea

³

Microbiological Resource Research Institute, Pusan National University, Busan 46241, Korea

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Viruses 2022, 14(10), 2313; https://doi.org/10.3390/v14102313

Submission received: 30 September 2022 / Revised: 18 October 2022 / Accepted: 19 October 2022 / Published: 21 October 2022

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Viral Infection 2023)

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Abstract

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.

Keywords: E6-associated protein; hepatitis B virus; proteasome; HBx; p53

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MDPI and ACS Style

Lim, H.-Y.; Han, J.; Yoon, H.; Jang, K.L. Tumor Suppressor p53 Inhibits Hepatitis B Virus Replication by Downregulating HBx via E6AP-Mediated Proteasomal Degradation in Human Hepatocellular Carcinoma Cell Lines. Viruses 2022, 14, 2313. https://doi.org/10.3390/v14102313

AMA Style

Lim H-Y, Han J, Yoon H, Jang KL. Tumor Suppressor p53 Inhibits Hepatitis B Virus Replication by Downregulating HBx via E6AP-Mediated Proteasomal Degradation in Human Hepatocellular Carcinoma Cell Lines. Viruses. 2022; 14(10):2313. https://doi.org/10.3390/v14102313

Chicago/Turabian Style

Lim, Ha-Yeon, Jiwoo Han, Hyunyoung Yoon, and Kyung Lib Jang. 2022. "Tumor Suppressor p53 Inhibits Hepatitis B Virus Replication by Downregulating HBx via E6AP-Mediated Proteasomal Degradation in Human Hepatocellular Carcinoma Cell Lines" Viruses 14, no. 10: 2313. https://doi.org/10.3390/v14102313

APA Style

Lim, H.-Y., Han, J., Yoon, H., & Jang, K. L. (2022). Tumor Suppressor p53 Inhibits Hepatitis B Virus Replication by Downregulating HBx via E6AP-Mediated Proteasomal Degradation in Human Hepatocellular Carcinoma Cell Lines. Viruses, 14(10), 2313. https://doi.org/10.3390/v14102313

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

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