Hepatitis B Virus HBx Protein Interactions with the Ubiquitin Proteasome System

Minor, Marissa; Slagle, Betty L.

doi:10.3390/v6114683

Cited by 67 publications

(54 citation statements)

References 116 publications

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“…An intriguing speculation coming from previous reports that the HBx-DDB1 interaction is critical for viral genome replication (15,16) was that HBx-targeted host factors that restrict viral DNA replication are regulated by the Cul4-DDB1 ubiquitin E3 ligase (12). Contrary to the expectation of that hypothesis, our findings consistently indicated that the DDB1-HBx interaction is largely dispensable for HBx-stimulated viral genome replication.…”

Section: Discussioncontrasting

confidence: 57%

“…The ␣-helical motif, referred to as the H box (i.e., residues 88 to 100), of the HBx polypeptide was revealed to be an interacting motif that binds directly to one of three ␤-propeller domains of DDB1 (i.e., the BPC domain) (11). Importantly, via its interaction with DDB1, HBx was shown to constitute the Cul4A-DDB1 ubiquitin E3 ligase, implicating a role of HBx in ubiquitin-mediated protein degradation (11,12). An intriguing possibility is that many, if not all, of these attributes of HBx could potentially be related to the DDB1-HBx interaction.…”

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confidence: 99%

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DDB1 Stimulates Viral Transcription of Hepatitis B Virus via HBx-Independent Mechanisms

Kim

Lee

Son

et al. 2016

J Virol

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HBx, a small regulatory protein of hepatitis B virus (HBV), augments viral DNA replication by stimulating viral transcription. Among numerous reported HBx-binding proteins, DDB1 has drawn attention, because DDB1 acts as a substrate receptor of the Cul4-DDB1 ubiquitin E3 ligase. Previous work reported that the DDB1-HBx interaction is indispensable for HBx-stimulated viral DNA replication, suggesting that the Cul4-DDB1 ubiquitin E3 ligase might target cellular restriction factors for ubiquitination and proteasomal degradation. To gain further insight into the DDB1-HBx interaction, we generated HBx mutants deficient for DDB1 binding (i.e., R96A, L98A, and G99A) and examined whether they support HBx-stimulated viral DNA replication. In contrast to data from previous reports, our results showed that the HBx mutants deficient for DDB1 binding supported viral DNA replication to nearly wild-type levels, revealing that the DDB1-HBx interaction is largely dispensable for HBx-stimulated viral DNA replication. Instead, we found that DDB1 directly stimulates viral transcription regardless of HBx expression. Through an HBV infection study, importantly, we demonstrated that DDB1 stimulates viral transcription from covalently closed circular DNA, a physiological template for viral transcription. Overall, we concluded that DDB1 stimulates viral transcription via a mechanism that does not involve an interaction with HBx. IMPORTANCEDDB1 constitutes a cullin-based ubiquitin E3 ligase, where DDB1 serves as an adaptor linking the cullin scaffold to the substrate receptor. Previous findings that the DDB1-binding ability of HBx is essential for HBx-stimulated viral DNA replication led to the hypothesis that HBx could downregulate host restriction factors that limit HBV replication through the cullin ubiquitin E3 ligase that requires the DDB1-HBx interaction. Consistent with this hypothesis, recent work identified Smc5/6 as a host restriction factor that is regulated by the viral cullin ubiquitin E3 ligase. In contrast, here we found that the DDB1-HBx interaction is largely dispensable for HBx-stimulated viral DNA replication. Instead, our results clearly showed that DDB1, regardless of HBx expression, enhances viral transcription. Overall, besides its role in the viral cullin ubiquitin E3 ligase, DDB1 itself stimulates viral transcription via HBx-independent mechanisms. H epatitis B virus (HBV) infection represents a major global public health concern, with over 300 million chronically infected patients worldwide. Chronic HBV infection carries a great risk of developing into severe liver diseases, including cirrhosis and liver cancer, which result in a million deaths annually (1). HBV carries a small (ca. 3.2-kb), relaxed circular (RC), partially double-stranded DNA. Following entry into the host cell, the viral RC DNA traffics to the nucleus, where it is converted into a covalently closed circular DNA (cccDNA), the template for viral transcription (2). Four viral RNAs are transcribed from their respective promoters and serve a...

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Section: Discussioncontrasting

confidence: 57%

mentioning

confidence: 99%

DDB1 Stimulates Viral Transcription of Hepatitis B Virus via HBx-Independent Mechanisms

Kim

Lee

Son

et al. 2016

J Virol

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“…Ubiquitin proteasome system (UPS), responsible for the degradation of a majority of intracellular proteins, is partially involved in this process [27]. HBx can interact with components of the UPS, including the CUL4 adaptor DDB1, the cullin regulatory complex CSN, and the 26S proteasome, and then alter the levels of target proteins [28]. Utilization of ubiquitin proteasome machinery by HBx has become one of the strategies for its promotion on HCC progression.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus X protein amplifies TGF-β promotion on HCC motility through down-regulating PPM1a

Liu

et al. 2016

Oncotarget

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Over-activation of transforming growth factor-β (TGF-β) signaling pathway promotes cell migration and invasion in hepatocellular carcinoma (HCC). The Hepatitis B virus X protein (HBx) is involved in the enhancement of TGF-β signaling pathway in HCC while the mechanism remains unclear. Protein phosphatase magnesium dependent 1A (PPM1a) functions as a phosphatase essential for terminating the TGF-β signaling pathway by dephosphorylating p-Smad2/3. In this study, we found that HBx dose-dependently downregulated PPM1a protein level in the presence of TGF-β, while having no effect on its mRNA level. Further study showed that HBx increased the ubiquitination of PPM1a and accelerated its proteasomal degradation. Restoration of PPM1a almost completely abrogated HBx mediated promotion on HCC migration and invasion. This involvement of PPM1a in HBx-related HCC was further confirmed with immunohistochemical analysis in HCC tissue. Compared with paired pericarcinous tissue, HCC tissue showed decreased PPM1a level. Besides, PPM1a level is negatively correlated with HBx expression. Taken together, our present study suggests that HBx-induced degradation of PPM1a is a novel mechanism for over-activation of TGF-β pathway in HCC development, which might provide potential candidates for clinical diagnosis and treatment.

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“…DNA tumor viruses, especially EBV, are well known to manipulate the host ubiquitin (Ub) machinery to facilitate their latent persistence and oncogenesis (16)(17)(18)(19)(20). We have provided solid evidence showing that IRF7 is activated by LMP1 through a TRAF6/RIP-dependent, K63-linked ubiquitination pathway (11,12).…”

mentioning

confidence: 84%

The Linear Ubiquitin Assembly Complex Modulates Latent Membrane Protein 1 Activation of NF-κB and Interferon Regulatory Factor 7

Wang

Zhao

Ren

et al. 2017

J Virol

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Recently, linear ubiquitin assembly complex (LUBAC)-mediated linear ubiquitination has come into focus due to its emerging role in activation of NF-B in different biological contexts. However, the role of LUBAC in LMP1 signaling leading to NF-B and interferon regulatory factor 7 (IRF7) activation has not been investigated. We show here that RNF31, the key component of LUBAC, interacts with LMP1 and IRF7 in Epstein-Barr virus (EBV)-transformed cells and that LUBAC stimulates linear ubiquitination of NEMO and IRF7. Consequently, LUBAC is required for LMP1 signaling to full activation of NF-B but inhibits LMP1-stimulated IRF7 transcriptional activity. The protein levels of RNF31 and LMP1 are correlated in EBV-transformed cells. Knockdown of RNF31 in EBV-transformed IB4 cells by RNA interference negatively regulates the expression of the genes downstream of LMP1 signaling and results in a decrease of cell proliferation. These lines of evidence indicate that LUBACmediated linear ubiquitination plays crucial roles in regulating LMP1 signaling and functions.IMPORTANCE We show here that LUBAC-mediated linear ubiquitination is required for LMP1 activation of NF-B but inhibits LMP1-mediated IRF7 activation. Our findings provide novel mechanisms underlying EBV-mediated oncogenesis and may have a broad impact on IRF7-mediated immune responses.

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Hepatitis B Virus HBx Protein Interactions with the Ubiquitin Proteasome System

Cited by 67 publications

References 116 publications

DDB1 Stimulates Viral Transcription of Hepatitis B Virus via HBx-Independent Mechanisms

DDB1 Stimulates Viral Transcription of Hepatitis B Virus via HBx-Independent Mechanisms

Hepatitis B virus X protein amplifies TGF-β promotion on HCC motility through down-regulating PPM1a

The Linear Ubiquitin Assembly Complex Modulates Latent Membrane Protein 1 Activation of NF-κB and Interferon Regulatory Factor 7

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