Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IRE1-alpha is an integral membrane protein of the endoplasmic reticulum (ER) that is a key sensor in the cellular transcriptional response to stress in the ER. Upon induction of ER stress, IRE1-alpha is activated, resulting in the synthesis of the active form of the transcription factor XBP1 via IRE1-mediated splicing of its mRNA. In this report, we have examined the role of IRE1-alpha and XBP1 in activation of the hepatitis B virus S promoter by ER stress. Cotransfection experiments revealed that overexpression of either IRE1-alpha or XBP1 activated this promoter. Conversely, cotransfected dominant-negative IRE1-alpha or small interfering RNA directed against XBP1 decreased the activation of the S promoter by ER stress, confirming an important role for the IRE1-alpha/XBP1 signaling pathway in activation of the S promoter. However, XBP1 does not bind directly to the S promoter; rather, a novel S promoter-binding complex that does not contain XBP1 is induced in cells undergoing ER stress in an XBP1-dependent manner. This complex, as well as transcriptional activation of the S promoter, is induced by ER stress in hepatocytes but not in fibroblasts, despite the presence of active XBP1 in the latter. Thus, the hepatitis B virus S promoter responds to a novel, cell type-restricted transcriptional pathway downstream of IRE1-alpha and XBP1.
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PMID:Activation of hepatitis B virus S promoter by a cell type-restricted IRE1-dependent pathway induced by endoplasmic reticulum stress. 1610

Numerous viruses including hepatitis B virus (HBV) induce endoplasmic reticulum (ER) stress, which interrupts protein folding causing accumulation of unfolded or misfolded proteins in ER. To alleviate the stress placed on ER, these proteins must be refolded or degraded by activating a specific cellular response known as ER stress response or unfolded protein response (UPR). Two UPR-specific signaling pathways involving transmembrane proteins ATF6 and XBP1 generate critical transcription factors that activate UPR-responsive genes. In this study, the role of the multifunctional regulatory protein of HBV (HBx protein) in activation of UPR was investigated. In Hep3B cells with transit or stable expression of HBx, XBP1 expression and ATF6 cleavage was observed, suggesting that the ATF6 and IRE1-XBP1 pathways were activated. Furthermore, these two pathways were also activated in HepG2.2.15 cells that constitutively replicate the intact HBV genome, and blocked at least partly by cotransfection with small interfering RNA (siRNA) expression plasmid that knocked down HBx expression. Our results clearly establish HBx as an inducer of UPR and the activator of the ATF6 and IRE1-XBP1 pathways of UPR. HBx-mediated activation of these pathways of UPR probably promote HBV replication and expression in liver cells, and contribute to liver pathogenesis, perhaps even to hepatocellular carcinoma (HCC) development.
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PMID:Hepatitis B virus X protein (HBx) activates ATF6 and IRE1-XBP1 pathways of unfolded protein response. 1709 96

The hepatitis B virus (HBV) large surface antigen (LHBS) mutant with deletion at the pre-S(2) region accumulates in endoplasmic reticulum (ER) and is associated with HBV-induced hepatocellular carcinogenesis. In this study, we found that the pre-S(2) LHBS mutant directly interacts with the Jun activation domain-binding protein 1 (JAB1). Association of pre-S(2) LHBS with JAB1 dissociated JAB1 from the JAB1/IRE1 complex in ER. The free (active) JAB1 then translocated into cell nuclei and rendered the Cdk inhibitor p27(Kip1) to cytosolic proteasome for degradation. The pre-S(2) LHBS mutant induced hyperphosphorylation of tumor suppressor retinoblastoma (RB) via cyclin-dependent kinase 2 (Cdk2), a downstream molecule regulated by p27(Kip1). This effect is independent of the ER stress signaling pathway. The transgenic mice carrying the pre-S(2) mutant LHBS gene also exhibited Cdk2 activation, p27(Kip1) degradation, as well as RB hyperphosphorylation. The mouse hepatocytes exhibited morphologic abnormalities such as chromatin condensation, multinucleation, and dysplasia of hepatocytes. In summary, the pre-S(2) LHBS mutant causes p27(Kip1) degradation through direct interaction with JAB1. The pre-S(2) mutant LHBS is suggested to be a potential oncoprotein for HBV-related hepatocellular carcinoma.
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PMID:Hepatitis B virus pre-S2 mutant surface antigen induces degradation of cyclin-dependent kinase inhibitor p27Kip1 through c-Jun activation domain-binding protein 1. 1795 6

Hepatitis B virus (HBV) belongs to the Hepadnaviridae family of enveloped DNA viruses. It was previously shown that HBV can induce endoplasmic reticulum (ER) stress and activate the IRE1-XBP1 pathway of the unfolded protein response (UPR), through the expression of the viral regulatory protein X (HBx). However, it remained obscure whether or not this activation had any functional consequences on the target genes of the UPR pathway. Of these targets, the ER degradation-enhancing, mannosidase-like proteins (EDEMs) are thought to play an important role in relieving the ER stress during UPR, by recognizing terminally misfolded glycoproteins and delivering them to the ER-associated degradation (ERAD). In this study, we investigated the role of EDEMs in the HBV life-cycle. We found that synthesis of EDEMs (EDEM1 and its homologues, EDEM2 and EDEM3) is significantly up-regulated in cells with persistent or transient HBV replication. Co-expression of the wild-type HBV envelope proteins with EDEM1 resulted in their massive degradation, a process reversed by EDEM1 silencing. Surprisingly, the autophagy/lysosomes, rather than the proteasome were involved in disposal of the HBV envelope proteins. Importantly, inhibition of the endogenous EDEM1 expression in HBV replicating cells significantly increased secretion of both, enveloped virus and subviral particles. This is the first report showing that HBV activates the ERAD pathway, which, in turn, reduces the amount of envelope proteins, possibly as a mechanism to control the level of virus particles in infected cells and facilitate the establishment of chronic infections.
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PMID:Activation of ERAD pathway by human hepatitis B virus modulates viral and subviral particle production. 2246 6

Hepatitis B is a major disease that chronically infects millions of people in the world, especially in developing countries. Currently, one of the effective vaccines to prevent Hepatitis B is the Hepatitis B Small Antigen (HBsAg), which is mainly produced by the recombinant yeast Saccharomyces cerevisiae. In order to bring down the price, which is still too high for people in developing countries to afford, it is important to understand key cellular processes that limit protein expression. In this study, we took advantage of yeast knockout collection (YKO) and screened 194 S. cerevisiae strains with single gene knocked out in four major steps of the protein secretory pathway, i.e., endoplasmic-reticulum (ER)-associated protein degradation, protein folding, unfolded protein response (UPR), and translocation and exocytosis. The screening showed that the single deletion of YPT32, SBH1, and HSP42 led to the most significant increase of HBsAg expression over the wild type while the deletion of IRE1 led to a profound decrease of HBsAg expression. The synergistic effects of gene knockout and gene overexpression were next tested. We found that simultaneously deleting YPT32 and overexpressing IRE1 led to a 2.12-fold increase in HBsAg expression over the wild type strain. The results of this study revealed novel genetic targets of protein secretory pathways that could potentially improve the manufacturing of broad scope vaccines in a cost-effective way using recombinant S. cerevisiae.
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PMID:Systematic Optimization of Protein Secretory Pathways in Saccharomyces cerevisiae to Increase Expression of Hepatitis B Small Antigen. 2855 91