Proteolytic Processing of the Hepatitis B Virus e Antigen Precursor

Messageot, Fabienne; Salhi, Samia; Eon, Patricia; Rossignol, Jean‐Michel

doi:10.1074/jbc.m207634200

Cited by 76 publications

(81 citation statements)

References 26 publications

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“…Taken together, these findings suggest that pcRNA levels alone do not impact HBeAg expression, even in the absence of host-adaptive immune responses. It will be important to investigate other factors that may be contributing to the differential HBeAg expression observed in these genotypes, such as posttranslational mechanisms, e.g., the processing and expression of precursory precore p25 and p22 proteins (27).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Studies Show that Sequence Variability Contributes to Marked Variation in Hepatitis B Virus Replication, Protein Expression, and Function Observed across Genotypes

Sozzi

Walsh

Littlejohn

et al. 2016

J Virol

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The hepatitis B virus (HBV) exists as 9 major genotypes (A to I), one minor strain (designated J) and multiple subtypes. Marked differences in HBV natural history, disease progression and treatment response are exhibited by many of these genotypes and subtypes. For example, HBV genotype C is associated with later hepatitis B e antigen (HBeAg) seroconversion and high rates of liver cancer compared to other HBV genotypes, whereas genotype A2 is rarely associated with HBeAg-negative disease or liver cancer. The reasons for these and other differences in HBV natural history are yet to be determined but could in part be due to sequence differences in the HBV genome that alter replicative capacity and/or gene expression. Direct comparative studies on HBV replication and protein expression have been limited to date due largely to the absence of infectious HBV cDNA clones for each of the HBV genotypes present in the same genetic arrangement. We have produced replication-competent infectious cDNA clones of the most common subtypes of genotypes A to D, namely, A2, B2, C2, D3, and the minor strain J, and compared their HBV replication phenotype using transient-transfection models. We identified striking differences in HBV replicative capacity as well as HBeAg and surface (HBsAg) protein expression across genotypes, which may in part be due to sequence variability in regulatory regions of the HBV genome. Functional analysis showed that sequence differences in the major upstream regulatory region across genotypes impacted promoter activity. IMPORTANCEThere have been very few studies directly comparing the replication phenotype of different HBV genotypes, for which there are marked differences in natural history and disease progression worldwide. We have generated replication-competent 1.3-mer cDNA clones of the major genotypes A2, B2, C2, and D3, as well as a recently identified strain J, and identified striking differences in replicative capacity and protein expression that may contribute to some of the observed differences in HBV natural history observed globally. Hepatitis B virus (HBV) is a major human health problem, with approximately 240 million people living with chronic hepatitis B (CHB) worldwide (1) and up to 1 million people dying each year from HBV-related liver conditions such as cirrhosis and liver cancer (2). HBV exists as nine genotypes worldwide (A to I), as well as a recently identified minor strain (designated J), with marked differences in natural history, pathogenesis, and treatment response observed across genotypes (3). These differences include the time to hepatitis B e antigen (HBeAg) seroconversion and the propensity for progression to serious liver disease such as liver cancer, both of which are greater for HBV genotype C (3). Genotypes differ by Ͼ8% in nucleotide sequence across the complete HBV genome, and within most genotypes multiple subtypes have also been identified that differ in nucleotide sequence by between 4 and 7.9% (3). The major genotypes worldwide are A to D, with genotypes...

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Section: Discussionmentioning

confidence: 99%

In Vitro Studies Show that Sequence Variability Contributes to Marked Variation in Hepatitis B Virus Replication, Protein Expression, and Function Observed across Genotypes

Sozzi

Walsh

Littlejohn

et al. 2016

J Virol

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“…In this context, it is important to note that many viral proteins are processed by pPCs (e.g., diverse fusion proteins including those from influenza A virus, respiratory syncytial virus, Ebola virus, severe acute respiratory syndrome virus, human CMV, hepatitis B virus, HIV) (13,26,47,48). It is obvious that under conditions of an acute infection these viral proteins will become highly abundant in the secretory compartments, and it has been shown that MHC I-presented viral Ags can originate from pPC-processed viral polypeptides (49).…”

Section: Discussionmentioning

confidence: 99%

Post-Endoplasmic Reticulum Rescue of Unstable MHC Class I Requires Proprotein Convertase PC7

Leonhardt

Fiegl

Rufer

et al. 2010

The Journal of Immunology

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The function of the peptide-loading complex (PLC) is to facilitate loading of MHC class I (MHC I) molecules with antigenic peptides in the endoplasmic reticulum and to drive the selection of these ligands toward a set of high-affinity binders. When the PLC fails to perform properly, as frequently observed in virus-infected or tumor cells, structurally unstable MHC I peptide complexes are generated, which are prone to disintegrate instead of presenting Ags to cytotoxic T cells. In this study we show that a second quality control checkpoint dependent on the serine protease proprotein convertase 7 (PC7) can rescue unstable MHC I, whereas the related convertase furin is completely dispensable. Cells with a malfunctioning PLC and silenced for PC7 have substantially reduced MHC I surface levels caused by high instability and significantly delayed surface accumulation of these molecules. Instead of acquiring stability along the secretory route, MHC I appears to get largely routed to lysosomes for degradation in these cells. Moreover, mass spectrometry analysis provides evidence that lack of PLC quality control and/or loss of PC7 expression alters the MHC I-presented peptide profile. Finally, using exogenously applied peptide precursors, we show that liberation of MHC I epitopes may directly require PC7. We demonstrate for the first time an important function for PC7 in MHC I-mediated Ag presentation.

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“…In turn, we and others have shown that the hepatitis B e antigen (HBeAg; p17) downregulates antiviral TLR2-and IL-1␤-mediated responses (5)(6)(7). HBeAg is secreted as a nonparticulate form of the hepatitis B virus (HBV) nucleocapsid protein (hepatitis B core antigen [HBcAg]; p21), which is processed from larger precore polyproteins (p25 and p22) (8). Although not required for HBV replication, the precore protein and HBeAg are critical for the establishment of persistent infection.…”

mentioning

confidence: 99%

Downregulation of Interleukin-18-Mediated Cell Signaling and Interferon Gamma Expression by the Hepatitis B Virus e Antigen

Jegaskanda

Ahn

Skinner

et al. 2014

J Virol

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The mechanisms by which hepatitis B virus (HBV) establishes and maintains chronic hepatitis B infection (CHBT he mechanisms by which hepatitis B virus (HBV) establishes and maintains persistent infection are not fully understood. It has become increasingly apparent that innate immune response via the effector functions of a range of cell types, including Kupffer cells, natural killer (NK) cells, and hepatocytes, play an important role in controlling HBV infection (1-3). Our group has previously shown that stimulation of the interleukin-1 (IL-1) and toll-like receptor 2 (TLR2) signaling pathways inhibits HBV replication in vitro (4). In turn, we and others have shown that the hepatitis B e antigen (HBeAg; p17) downregulates antiviral TLR2-and IL-1␤-mediated responses (5-7). HBeAg is secreted as a nonparticulate form of the hepatitis B virus (HBV) nucleocapsid protein (hepatitis B core antigen [HBcAg]; p21), which is processed from larger precore polyproteins (p25 and p22) (8). Although not required for HBV replication, the precore protein and HBeAg are critical for the establishment of persistent infection. The HBV precore protein and HBeAg are important regulators of innate and adaptive immune responses that contribute to the establishment and/or maintenance of persistent infection.IL-18 is a proinflammatory cytokine synthesized and secreted by mononuclear cells, including Kupffer cells. In the presence of the necessary costimulatory ligands, such as IL-12 (9), IL-18 stimulates IFN-␥ production by NK cells, T cells, dendritic cells (DCs), and B cells. IL-18 signaling is activated following the interaction of two receptors: the alpha-receptor, IL-18R1, and the beta-receptor, AcPL, both of which dimerize following ligand binding to the alpha component, initiating signal transduction by AcPL (10). Murine studies have shown that IL-18 (11) inhibits HBV replication through induction of IFN-␥ (12, 13), which directly inhibits the HBV life cycle at the pre-and posttranslational level. In vitro studies have recently shown that, similar to IL-1 (4), overexpression of IL-18 inhibits HBV replication in a hepatoma cell line (14), although the mechanism for this inhibition is unclear, as hepatocytes do not produce IFN-␥.NK cells are lymphocytes that eliminate virus-infected cells by both direct cytolysis and the production of several antiviral cytokines, including IFN-␥. HBV infection stimulates NK cells, most likely via the activation of DCs and macrophages that produce and chemokines, including CXCR3 (15). NK cells

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Proteolytic Processing of the Hepatitis B Virus e Antigen Precursor

Cited by 76 publications

References 26 publications

In Vitro Studies Show that Sequence Variability Contributes to Marked Variation in Hepatitis B Virus Replication, Protein Expression, and Function Observed across Genotypes

In Vitro Studies Show that Sequence Variability Contributes to Marked Variation in Hepatitis B Virus Replication, Protein Expression, and Function Observed across Genotypes

Post-Endoplasmic Reticulum Rescue of Unstable MHC Class I Requires Proprotein Convertase PC7

Downregulation of Interleukin-18-Mediated Cell Signaling and Interferon Gamma Expression by the Hepatitis B Virus e Antigen

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