Hepatitis B virus X protein activates E3 ubiquitin ligase Siah-1 to control virus propagation via a negative feedback loop

Yeom, Sujeong; Kim, Soo Shin; Jeong, Hyerin; Jang, Kyung Lib

doi:10.1099/jgv.0.000856

Cited by 22 publications

(51 citation statements)

References 60 publications

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“…HBx is also known to induce accumulation of γ-H2AX, a marker of DNA double-strand breaks [18], suggesting that HBx activates p53 via modulation of DNA damage signalling pathways. Indeed, HBx subsequently activates ATM and CHK-2 via phosphorylation of the Ser-1981 and Thr-68 residues, respectively, which leads to activation of p53 via phosphorylation of the Ser-15 and Ser-20 residues [19,31]. The present study consistently showed that HBx upregulates p53 levels in order to upregulate PA28γ levels in human hepatoma cells (Fig.…”

Section: Discussionsupporting

confidence: 70%

“…Several studies have shown that HBx upregulates p53 levels to stimulate the expression of target genes, such as p21, Siah-1, PA28γ and several pro-apoptotic genes, including Bax, Fas and Nox [18,19,21,23,28]. In addition to this effect, HBx alters the mitochondrial membrane potential to increase levels of cellular reactive oxygen species [29,30].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that HBx upregulates p53 levels via activation of the ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (CHK2) pathway and enhances its transcriptional activity [18,19]. In addition, p53 activates PA28γ transcription through p53 response elements located within its promoter [20].…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis B virus X protein stimulates cell growth by downregulating p16 levels via PA28γ-mediated proteasomal degradation

Cha

Jang

2020

Journal of General Virology

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Proteasomal activator 28 gamma (PA28γ), an essential constituent of the 20S proteasome responsible for ubiquitinindependent degradation of target proteins, is frequently overexpressed in hepatocellular carcinoma. Recently, we have reported that hepatitis B virus (HBV) X protein (HBx) activates PA28γ expression in human hepatocytes via upregulation of p53 levels; however, its role in HBV tumorigenesis remains unknown. Here, we found that HBx-activated PA28γ downregulates p16 levels via ubiquitin-independent proteasomal degradation. As a result, HBx activated the Rb-E2F pathway and stimulated G 1 /S cell cycle progression, resulting in an increase in cell proliferation. The potential of HBx to induce these effects was reproduced in a 1.2-mer HBV replicon and in in vitro HBV infection systems and was almost completely abolished by either PA28γ knockdown or p16 overexpression, demonstrating the critical role of the PA28γ-mediated p16 degradation in HBV tumorigenesis.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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Hepatitis B virus X protein stimulates cell growth by downregulating p16 levels via PA28γ-mediated proteasomal degradation

Cha

Jang

2020

Journal of General Virology

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“…Furthermore, recent studies have indicated that several special cellular proteins as restriction factors limit HBV replication by repressing the expression of HBx via the UPS. For example, the tumor suppressor p53 could induce Ub-dependent proteasomal degradation of HBx [31], through an E3 ligase, seven in absentia homologue 1 (Siah-1) [22]. Ling et al showed that Id-1 [32], a member of the HLH protein family, was capable of interacting with proteasome subunit C8 (PMSC8), to facilitate the degradation of HBx.…”

Section: Main Textmentioning

confidence: 99%

The interaction of hepatitis B virus with the ubiquitin proteasome system in viral replication and associated pathogenesis

Kong

You

Kong

et al. 2019

Virol J

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Background The ubiquitin proteasome system (UPS) regulates the expression levels of cellular proteins by ubiquitination of protein substrates followed by their degradation via the proteasome. As a highly conserved cellular degradation mechanism, the UPS affects a variety of biological processes and participates in viral propagation. Main body During hepatitis B virus (HBV) infection, the UPS is shown to act as a double-edged sword in viral pathogenesis. On the one hand, the UPS acts as a host defense mechanism to selectively recognize HBV proteins as well as special cellular proteins that favor the viral life cycle and induces their ubiquitin-dependent proteasomal degradation to limit HBV infection. On the other hand, the HBV has evolved to subvert the UPS function for its own advantage. Moreover, in the infected hepatocytes, certain cellular proteins that are dependent on the UPS are involved in abnormal biological processes which are mediated by HBV. Conclusion The molecular interaction of HBV with the UPS to modulate viral propagation and pathogenesis is summarized in the review. Considering the important role of the UPS in HBV infection, a better understanding of the HBV-UPS interaction could provide novel insight into the mechanisms that are involved in viral replication and pathogenesis and help to develop potential treatment strategies targeting the UPS.

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“…Hence, HBx protein-mediated p53 inactivation might induce persistant liver inflammation that is not for HBV elimination. Certainly, p53 can mediate HBx protein inactivation through MDM2-dependent ubiquitin degradation and even seven in absentia homolog 1 (Siah-1) proteindependent proteasomal degradation 66,67 . However, HBx protein has its defense mechanism by directly binding to MDM2 and promoting MDM2 translocation into the nucleus to antagonize p53 transcriptional activity 68 .…”

Section: Hbv-induced Hepatoma Cell Transformationmentioning

confidence: 99%

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

et al. 2020

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Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2-p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2-p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes' transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4 + T cells by disrupting their MDM2-p53 axis. Moreover, inefficiency of hepatic immune response can be further aggravated when hepatitis viruses co-infected with HIV. Unlike with chronic viral infections, MDM2-p53 axis might play a dual role in glucolipid metabolism of hepatocytes, which presented with enhancing glucolipid catabolism, but promoting hepatocyte injury at the early and late stages of glucolipid metabolism disorder. Oxidative stress, fatty degeneration, and abnormal cell growth can be detected in hepatocytes that were suffering from glucolipid metabolism disorder, and all of which could contribute to HCC initiation. In this review, we focus on the current studies of the MDM2-p53 axis in HCC, and specifically discuss the impact of MDM2-p53 axis dysfunction by viral infection and metabolic disease in the transformation of normal hepatocytes into hepatoma cells. We also discuss the therapeutic avenues and potential targets that are being developed to normalize the MDM2-p53 axis in HCC.

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Hepatitis B virus X protein activates E3 ubiquitin ligase Siah-1 to control virus propagation via a negative feedback loop

Cited by 22 publications

References 60 publications

Hepatitis B virus X protein stimulates cell growth by downregulating p16 levels via PA28γ-mediated proteasomal degradation

Hepatitis B virus X protein stimulates cell growth by downregulating p16 levels via PA28γ-mediated proteasomal degradation

The interaction of hepatitis B virus with the ubiquitin proteasome system in viral replication and associated pathogenesis

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

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