Hepatitis B virus polymerase inhibits the interferon-inducible MyD88 promoter by blocking nuclear translocation of Stat1

Wu, Min; Xu, Yu; Lin, Shujing; Zhang, Xiaonan; Li, Xiang; Yuan, Zhenghong

doi:10.1099/vir.0.82959-0

Cited by 82 publications

(72 citation statements)

References 27 publications

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“…There are multiple reports implicating HBV Pol in modulating the host innate immune response, but none of these reports indicate the involvement of the mitochondria in manifesting these effects of Pol. Specifically, HBV Pol has been reported to reduce the response to type I IFN signaling by blocking NF-B, IRF3, and Stat1 nuclear translocation (25,26,72). Further, RIG-I has been identified as a direct antiviral sensor for the Ep stem-loop on the pgRNA to repress HBV replication.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus Polymerase Localizes to the Mitochondria, and Its Terminal Protein Domain Contains the Mitochondrial Targeting Signal

Unchwaniwala

Sherer

Loeb

2016

J Virol

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To understand subcellular sites of hepatitis B virus (HBV) replication, we visualized core (Cp), polymerase (Pol), and pregenomic RNA (pgRNA) in infected cells. Interestingly, we found that the majority of Pol localized to the mitochondria in cells undergoing viral replication. The mitochondrial localization of Pol was independent of both the cell type and other viral components, indicating that Pol contains an intrinsic mitochondrial targeting signal (MTS). Neither Cp nor pgRNA localized to the mitochondria during active replication, suggesting a role other than DNA synthesis for Pol at the mitochondria. The Pol of duck hepatitis B virus (DHBV) also localized to the mitochondria. This result indicates that localization of Pol to mitochondria is likely a feature of all hepadnaviruses. To map the MTS within HBV Pol, we generated a series of Pol-green fluorescent protein (Pol-GFP) fusions and found that a stretch spanning amino acids (aa) 141 to 160 of Pol was sufficient to target GFP to the mitochondria. Surprisingly, deleting aa 141 to 160 in full-length Pol did not fully ablate Pol's mitochondrial localization, suggesting that additional sequences are involved in mitochondrial targeting. Only by deleting the N-terminal 160 amino acids in fulllength Pol was mitochondrial localization ablated. Crucial residues for pgRNA packaging are contained within aa 141 to 160, indicating a multifunctional role of this region of Pol in the viral life cycle. Our studies show an unexpected Pol trafficking behavior that is uncoupled from its role in viral DNA synthesis. IMPORTANCEChronic infection by HBV is a serious health concern. Existing therapies for chronically infected individuals are not curative, underscoring the need for a better understanding of the viral life cycle to develop better antiviral therapies. To date, the most thoroughly studied function of Pol is to package the pgRNA and reverse transcribe it to double-stranded DNA within capsids. This study provides evidence for mitochondrial localization of Pol and defines the MTS. Recent findings have implicated a nonreverse transcription role for Pol in evading host innate immune responses. Mitochondria play an important role in controlling cellular metabolism, apoptosis, and innate immunity. Pol may alter one or more of these host mitochondrial functions to gain a replicative advantage and persist in chronically infected individuals.

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Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus Polymerase Localizes to the Mitochondria, and Its Terminal Protein Domain Contains the Mitochondrial Targeting Signal

Unchwaniwala

Sherer

Loeb

2016

J Virol

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“…For example, evidence has been obtained that the HBV polymerase can interfere with IRF-3 and IRF-7 signaling by binding to the RNA helicase DDX3 (Fig. 1) (Foster et al 1991;Christen et al 2007;Wu et al 2007;Wang and Ryu 2010;Yu et al 2010).…”

Section: Innate Immunity During Hbv Infection: Recognition Defect or mentioning

confidence: 99%

Immune Response in Hepatitis B Virus Infection

Tan

Koh

Bertoletti

2015

Cold Spring Harb Perspect Med

102

104

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Hepatitis B virus (HBV) can replicate within hepatocytes without causing direct cell damage. The host immune response is, therefore, not only essential to control the spread of virus infection, but it is also responsible for the inflammatory events causing liver pathologies. In this review, we discuss how HBV deals with host immunity and how we can harness it to achieve virus control and suppress liver damage.

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“…Luciferase assays were performed as described previously (50). For chloramphenicol acetyltransferase (CAT) assays, Huh7 cells were transfected with the indicated plasmids.…”

Section: Plasmids and Virusesmentioning

confidence: 99%

“…We and others have shown that MyD88 expression can be induced by IFN-␣ and that MyD88 has an antiviral activity against HBV in hepatoma cells that is mediated by nuclear factor B (NF-B) activation (12,25,51,52). To counteract its inhibition, the HBV polymerase dampens the activation of the MyD88 promoter by blocking the nuclear translocation of Stat1, thereby reducing IFN-␣-inducible MyD88 expression (50), further suggesting a critical role for MyD88 in antiviral activity against HBV. The aim of the present study was to further investigate the antiviral activity of MyD88 and the mechanism of action.…”

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confidence: 99%

Inhibition of Hepatitis B Virus Replication by MyD88 Involves Accelerated Degradation of Pregenomic RNA and Nuclear Retention of Pre-S/S RNAs

Lin

Chen

et al. 2010

J Virol

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Myeloid differentiation primary response protein 88 (MyD88), which can be induced by alpha interferon (IFN-␣), has an antiviral activity against the hepatitis B virus (HBV). The mechanism of this antiviral activity remains poorly understood. Here, we report that MyD88 inhibited HBV replication in HepG2.2.15 cells and in a mouse model. The knockdown of MyD88 expression weakened the IFN-␣-induced inhibition of HBV replication. Furthermore, MyD88 posttranscriptionally reduced the levels of viral RNA. Remarkably, MyD88 accelerated the decay of viral pregenomic RNA in the cytoplasm. Mapping analysis showed that the RNA sequence located in the 5-proximal region of the pregenomic RNA was critical for the decay. In addition, MyD88 inhibited the nuclear export of pre-S/S RNAs via the posttranscriptional regulatory element (PRE). The retained pre-S/S RNAs were shown to degrade in the nucleus. Finally, we found that MyD88 inhibited the expression of polypyrimidine tract-binding protein (PTB), a key nuclear export factor for PRE-containing RNA. Taken together, our results define a novel antiviral mechanism against HBV mediated by MyD88.Hepatitis B virus (HBV) is a noncytopathic, enveloped virus with a circular, double-stranded DNA genome. It causes both acute and chronic infection of the human liver. Although a highly effective preventive vaccine is now available, HBV infection remains a major health problem worldwide. It is estimated that chronic HBV infection affects 350 to 400 million people globally, about a quarter of whom will eventually develop severe liver diseases, including liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC) (4).Current antiviral therapies involve the use of nucleoside analogs and alpha interferon (IFN-␣) (28). IFN-␣, a type I interferon, engages the IFN-␣ receptor complex to activate the Jak/Stat pathway and trigger the transcription of a diverse set of genes, referred to as IFN-stimulated genes (ISGs) (2, 40). In total, the gene products of ISGs establish an antiviral response in target cells (2, 40). IFN-␣ inhibits HBV replication through a variety of mechanisms. It was reported previously that IFN-␣ can suppress viral gene expression, prevent the formation of viral RNA-containing core particles, and reduce the accumulation of viral replicative intermediates (11,35,37,(46)(47)(48). Importantly, the precise antiviral mechanism of IFN-␣ and the biological functions of many ISGs have not been fully elucidated.Myeloid differentiation primary response protein 88 (MyD88) is a key adaptor in the signaling cascade of the innate immune response (22). We and others have shown that MyD88 expression can be induced by IFN-␣ and that MyD88 has an antiviral activity against HBV in hepatoma cells that is mediated by nuclear factor B (NF-B) activation (12, 25, 51, 52). To counteract its inhibition, the HBV polymerase dampens the activation of the MyD88 promoter by blocking the nuclear translocation of Stat1, thereby reducing IFN-␣-inducible MyD88 expression (50), further suggesting a critical rol...

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Hepatitis B virus polymerase inhibits the interferon-inducible MyD88 promoter by blocking nuclear translocation of Stat1

Cited by 82 publications

References 27 publications

Hepatitis B Virus Polymerase Localizes to the Mitochondria, and Its Terminal Protein Domain Contains the Mitochondrial Targeting Signal

Hepatitis B Virus Polymerase Localizes to the Mitochondria, and Its Terminal Protein Domain Contains the Mitochondrial Targeting Signal

Immune Response in Hepatitis B Virus Infection

Inhibition of Hepatitis B Virus Replication by MyD88 Involves Accelerated Degradation of Pregenomic RNA and Nuclear Retention of Pre-S/S RNAs

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