Inhibition of Cellular Proteasome Activities Mediates HBX-Independent Hepatitis B Virus Replication
            <i>In Vivo</i>

Zhang, Zhensheng; Sun, Eun Gene; Ou, Jing-Hsiung; Liang, T. Jake

doi:10.1128/jvi.00579-10

Cited by 19 publications

(16 citation statements)

References 31 publications

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“…It has been reported that the proteasome controlled HBV replication both in cell culture systems and in a mouse model (47,48). In our study, we revealed that the proteasome controlled HBV polymerase expression (Fig.…”

Section: Fig 6 Polymerase Binds Ciap2 (A)supporting

confidence: 57%

Inhibition of Hepatitis B Virus Replication by cIAP2 Involves Accelerating the Ubiquitin-Proteasome-Mediated Destruction of Polymerase

Wang

et al. 2011

J Virol

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Cellular inhibitor of apoptosis protein 2 (cIAP2) is a potent suppressor of apoptotic cell death. We have shown previously that cIAP2 is involved in the tumor necrosis factor alpha (TNF-␣)-induced anti-hepatitis B virus (HBV) response; however, the mechanism for this antiviral effect remains unclear. In the present study, we demonstrate that cIAP2 can significantly reduce the levels of HBV DNA replication intermediates but not the total viral RNA or core protein levels. Domain-mapping analysis revealed that the carboxy-terminal domains of cIAP2 were indispensable for this anti-HBV ability and that an E3 ligase-deficient mutant of cIAP2 (termed cIAP2*) completely lost its antiviral activity. We further identified HBV polymerase as the target of cIAP2. Overexpression of cIAP2 but not cIAP2* reduced polymerase protein levels, while cIAP2 knockdown increased polymerase expression. In addition, we observed that cIAP2 promoted the degradation of the viral polymerase through a proteasome-dependent pathway. Further experiments demonstrated that cIAP2 can bind to polymerase and promote its polyubiquitylation. Finally, we found that cIAP2 downregulated the encapsidation of HBV pregenomic RNA. Taken together, these data reveal a novel mechanism for the inhibition of HBV replication by cIAP2 via acceleration of the ubiquitin-proteasome-mediated decay of polymerase and reduction of the encapsidation of HBV pregenomic RNA, making this mechanism a novel strategy for HBV therapy.Infection with hepatitis B virus (HBV) is a public health problem worldwide. It is estimated that at least 10% of the population of tropical Africa and Far East Asia are chronic carriers of the virus (40). Epidemiological studies have estimated that 350 million people are chronic carriers of HBV, with the potential to develop chronic active hepatitis, liver cirrhosis, or hepatocellular carcinoma (HCC) (9). HBV is a small double-stranded DNA virus belonging to the family Hepadnaviridae and replicates primarily in hepatocytes. In the nuclei of hepatocytes, the covalently closed circular DNA (cccDNA) of HBV serves as the transcription template for the viral pregenomic RNA (pgRNA) and subgenomic RNAs. The pgRNA is a multifunctional transcript. This transcript encodes the viral polymerase and core protein while also functioning as the template for HBV reverse transcription. HBV genome replication is initiated upon the recognition and binding of pgRNA by the viral polymerase protein. The complex formed by pgRNA and polymerase is then packaged into nucleocapsids, and in the nucleocapsids, polymerase catalyzes the conversion of pgRNA into single-stranded DNA (ssDNA) and relaxed circular DNA (rcDNA). The mature nucleocapsids are then enveloped and secreted (37).

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Section: Fig 6 Polymerase Binds Ciap2 (A)supporting

confidence: 57%

Inhibition of Hepatitis B Virus Replication by cIAP2 Involves Accelerating the Ubiquitin-Proteasome-Mediated Destruction of Polymerase

Wang

et al. 2011

J Virol

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“…Moreover proteasome inhibition was shown to enhance HBV replication in cell culture and in mice models (Zhang et al, 2004;Zhang et al, 2010). Indeed, in the presence of proteasome inhibitors, the replication of the wildtype virus was not affected, while the replication of the HBx-negative virus was enhanced and restored to the wild-type level (Zhang et al, 2004;Zhang et al, 2010). Thus HBx may functions through the inhibition of proteasome activities to enhance HBV replication.…”

Section: Hbx Influences Many Cellular Processesmentioning

confidence: 97%

“…Different groups using different models showed that HBx may localize and interact with the proteasome components thereby influencing proteasome subunit composition (Chen et al, 2001;Fischer et al, 1995;Hu et al, 1999;Zhang et al, 2000). Moreover proteasome inhibition was shown to enhance HBV replication in cell culture and in mice models (Zhang et al, 2004;Zhang et al, 2010). Indeed, in the presence of proteasome inhibitors, the replication of the wildtype virus was not affected, while the replication of the HBx-negative virus was enhanced and restored to the wild-type level (Zhang et al, 2004;Zhang et al, 2010).…”

Section: Hbx Influences Many Cellular Processesmentioning

confidence: 99%

Hepatitis B Virus X Protein: A Key Regulator of the Virus Life Cycle

Protzer¹

2012

Viral Genomes - Molecular Structure, Diversity, Gene Expression Mechanisms and Host-Virus Interactions

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“…Previous studies have indicated that HBx is degraded in a ubiquitin-proteasome pathway (56,57). In addition, previous studies have demonstrated that HBx may be highly expressed in HepG2 cells transiently transfected with HBx expression plasmids, but its expression in the HBx expression stable cell line is weak (54,58).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus X protein promotes hepatocellular carcinoma invasion and metastasis via upregulating thioredoxin interacting protein

Nong

et al. 2017

Oncology Letters

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Abstract. Hepatitis B virus X protein (HBx), a multifunctional protein encoded by the X gene of the hepatitis B virus (HBV) is involved in the metastasis of HBV-associated hepatocellular carcinoma (HCC) through various pathways, including upregulating intracellular reactive oxygen species (ROS). Thioredoxin interacting protein (TXNIP) is a key mediator of intracellular ROS, but its function in HBx-mediated metastasis of HBV-associated HCC is elusive. In the present study, HBV-associated HCC tissues with or without metastasis and HepG2 cells were used to study the function of TXNIP in HBx-mediated metastasis of HBV-associated HCC. Initially, the expression levels of TXNIP and HBx in HBV-associated HCC tissues were detected by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction. The results revealed that high expression of TXNIP may be an independent risk factor for metastasis of HBV-associated HCC, and the mRNA levels of TXNIP and HBx were positively associated. Secondly, the association between HBx and TXNIP was investigated using a HBx expression stable cell line, in which HBx expression was induced and controlled by doxycycline. The results demonstrated that HBx may upregulate TXNIP expression in HepG2 cells. Thirdly, the effects of TXNIP and HBx on HepG2 cell migration and invasion were studied by scratch and Matrigel invasion assays, respectively. The results demonstrated that TXNIP overexpression enhanced HepG2 cell migration and invasion. In addition, ectopic expression of HBx promoted HepG2 cell migration and invasion, and this effect may be attenuated by knockdown of TXNIP expression, which indicated that TXNIP may be involved in the process. In summary, the present results demonstrated that TXNIP may be involved in HBx-mediated metastasis of HBV-associated HCC.

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Inhibition of Cellular Proteasome Activities Mediates HBX-Independent Hepatitis B Virus Replication In Vivo

Cited by 19 publications

References 31 publications

Inhibition of Hepatitis B Virus Replication by cIAP2 Involves Accelerating the Ubiquitin-Proteasome-Mediated Destruction of Polymerase

Inhibition of Hepatitis B Virus Replication by cIAP2 Involves Accelerating the Ubiquitin-Proteasome-Mediated Destruction of Polymerase

Hepatitis B Virus X Protein: A Key Regulator of the Virus Life Cycle

Hepatitis B virus X protein promotes hepatocellular carcinoma invasion and metastasis via upregulating thioredoxin interacting protein

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