HBx natural variants containing Ser-101 instead of Pro-101 evade ubiquitin-dependent proteasomal degradation by activating proteasomal activator 28 gamma expression

Jeong, Hyerin; Cha, Sungkyung; Jang, Kyung Lib

doi:10.1099/jgv.0.001337

Cited by 5 publications

(4 citation statements)

References 47 publications

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“…In addition, HCV core protein did not affect the levels of intracellular HBV proteins and extracellular virus particles derived from the 1.2-mer WT in Hep3B cells (). Consistent with previous reports [39, 49] and data shown in , ectopic p53 expression in Hep3B cells upregulated the levels of intracellular HBV proteins and extracellular virus particles derived from 1.2-mer WT, whereas ectopic p53 upregulated Siah-1 levels in these cells (). HCV core protein further upregulated Siah-1 levels via the activation of ectopic p53, resulting in a dramatic decrease in the levels of the intracellular HBV proteins and extracellular virus particles derived from 1.2-mer WT in Hep3B cells ().…”

Section: Resultssupporting

confidence: 92%

“…1d, f). Consistent with previous reports [39,49] and data shown in Fig. 2(c), ectopic p53 expression in Hep3B cells upregulated the levels of intracellular HBV proteins and extracellular virus particles derived from 1.2-mer WT, whereas ectopic p53 upregulated Siah-1 levels in these cells (Fig.…”

Section: Hcv Core Protein Downregulates Hbx Levels To Inhibit Hbv Replication In a 12-mer Hbv Replicon Systemsupporting

confidence: 92%

“…In addition, HBx levels were affected differentially in Hep3B cells depending on the levels of the ectopic p53 (Figs 1c and 2d), although the mechanism is unknown. According to previous reports, HBx variants with Ser-101 instead of Pro-101 upregulated p53 levels and thus are more susceptible to Siah-1-mediated ubiquitination in human hepatoma cells [30, 49]. It should also be considered whether HBV/HCV coinfection was established as a result of simultaneous infection with two viruses or superinfection with HBV or HCV.…”

Section: Discussionmentioning

confidence: 99%

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Hepatitis C virus core protein inhibits hepatitis B virus replication by downregulating HBx levels via Siah-1-mediated proteasomal degradation during coinfection

Lee

Yoon

Han

et al. 2021

Journal of General Virology

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Most clinical and experimental studies have suggested that hepatitis C virus (HCV) is dominant over hepatitis B virus (HBV) during coinfection, although the mechanism remains unclear. Here, we found that HCV core protein inhibits HBV replication by downregulating HBx levels during coinfection in human hepatoma cells. For this effect, HCV core protein increased reactive oxygen species levels in the mitochondria and activated the ataxia telangiectasia mutated-checkpoint kinase two pathway in the nucleus, resulting in an upregulation of p53 levels. Accordingly, HCV core protein induced p53-dependent activation of seven in absentia homolog one expression, an E3 ligase of HBx, resulting in the ubiquitination and proteasomal degradation of HBx. The effect of the HCV core protein on HBx levels was accurately reproduced in both a 1.2-mer HBV replicon and in vitro HBV infection systems, providing evidence for the inhibition of HBV replication by HCV core protein. The present study may provide insights into the mechanism of HCV dominance in HBV- and HCV-coinfected patients.

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Section: Resultssupporting

confidence: 92%

Section: Hcv Core Protein Downregulates Hbx Levels To Inhibit Hbv Replication In a 12-mer Hbv Replicon Systemsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Hepatitis C virus core protein inhibits hepatitis B virus replication by downregulating HBx levels via Siah-1-mediated proteasomal degradation during coinfection

Lee

Yoon

Han

et al. 2021

Journal of General Virology

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“…Previous reports have demonstrated that HBx levels are primarily regulated by the UPS [ 17 , 44 ]. Therefore, we first examined whether p53 decreased the stability of HBx in human hepatoma cells.…”

Section: Resultsmentioning

confidence: 99%

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

Lim

Han

Yoon

et al. 2022

Viruses

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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.

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Proteasomal activator 28 gamma stabilizes hepatitis B virus X protein by competitively inhibiting the Siah-1-mediated proteasomal degradation

Han

Kim

Jeong

et al. 2021

Biochemical and Biophysical Research Communications

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HBx natural variants containing Ser-101 instead of Pro-101 evade ubiquitin-dependent proteasomal degradation by activating proteasomal activator 28 gamma expression

Cited by 5 publications

References 47 publications

Hepatitis C virus core protein inhibits hepatitis B virus replication by downregulating HBx levels via Siah-1-mediated proteasomal degradation during coinfection

Hepatitis C virus core protein inhibits hepatitis B virus replication by downregulating HBx levels via Siah-1-mediated proteasomal degradation during coinfection

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

Proteasomal activator 28 gamma stabilizes hepatitis B virus X protein by competitively inhibiting the Siah-1-mediated proteasomal degradation

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