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)

Two-hybrid protein interaction screening in yeast was used to identify proteins that interact with the HBx nonstructural protein of hepatitis B virus (HBV). A new human member of the proteasome alpha-subunit family was obtained. Its protein sequence closely resembles the 28 kD subunits from other organisms. The interaction with HBx was abolished by a two amino-acid insertion behind position 128 in HBx, in a region previously found to be essential for its transcriptional transactivation function. These data support a model of HBx acting indirectly on transcriptional processes. By binding to a specific proteasome alpha-subunit, HBx might interfere with degradative processes, thereby enhancing the half-life of different transcription factors and other nuclear regulatory proteins. Interaction with the Hu 28k proteasome subunit could thus provide a unifying explanation for the markedly pleiotropic effects of HBx.
 ...
PMID:HBx protein of hepatitis B virus interacts with the C-terminal portion of a novel human proteasome alpha-subunit. 748 96

Although the biological importance of hepatitis B virus X protein (HBX) in the life cycle of hepatitis B virus has been well established, the cellular and molecular basis of its function remains largely undefined. Despite the association of multiple activities with HBX, none of them appear to provide a unifying hypothesis regarding the true biological function of HBX. Identification and characterization of cellular targets of HBX remain an essential goal in the elucidation of the molecular mechanisms of HBX. Using the Saccharomyces cerevisiae two-hybrid system, we have identified and characterized a novel subunit of the proteasome complex (XAPC7) that interacts specifically with HBX. We also showed that HBX binds specifically to XAPC7 in vitro. Mutagenesis studies have defined the domains of interaction to be critical for the function of HBX. Furthermore, overexpression of XAPC7 appeared to activate transcription by itself and antisense expression of XAPC7 was able to block transactivation by HBX. Therefore, the proteasome complex is possibly a functional target of HBX in cells.
 ...
PMID:Proteasome complex as a potential cellular target of hepatitis B virus X protein. 876 72

Although the biological importance of hepatitis B virus X protein (HBX) in the life cycle of hepatitis B virus has been well established, the cellular and molecular basis of its function remains largely undefined. Despite the association of multiple activities with HBX, none of them appear to provide a unifying hypothesis regarding the true biological function of HBX. Identification and characterization of cellular targets of HBX remain an essential goal in the elucidation of the molecular mechanisms of HBX. Using the Saccharomyces cerevisiae two-hybrid system, we have identified and characterized a novel subunit of the proteasome complex (XAPC7) that interacts specifically with HBX. We also showed that HBX binds specifically to XAPC7 in vitro. Mutagenesis studies have defined the domains of interaction to be critical for the function of HBX. Furthermore, overexpression of XAPC7 appeared to activate transcription by itself and antisense expression of XAPC7 was able to block transactivation by HBX. Therefore, the proteasome complex is possibly a functional target of HBX in cells.
 ...
PMID:The hepatitis B virus X protein: the quest for a role in viral replication and pathogenesis. 902 71

Chronic infection with hepatitis B virus is associated with a high incidence of liver diseases, including hepatocellular carcinoma. Hepatitis-B-virus-encoded X antigen (HBxAg) stimulates virus gene expression and replication, which may be important for the establishment and maintenance of the chronic carrier state. Integration of viral DNA encoding HBxAg during chronic infection results in increased X antigen expression. HBxAg overexpression may alter signal transduction pathways important for the regulation of cell growth during hepatocellular regeneration. The finding that HBxAg binds to and inactivates negative growth-regulatory molecules, such as the tumor suppressor p53, suggests additional ways that HBxAg may act in hepatocarcinogenesis. HBxAg may also stimulate the expression of positive growth regulators, such as insulin-like growth factor II and the insulin-like growth factor I receptor. The finding that HBxAg may compromise DNA repair and that it may effect the normal turnover of growth-regulatory molecules in the proteasome may also contribute to its carcinogenic properties. Hence, HBxAg may contribute to the pathogenesis of chronic infection and development of hepatocellular carcinoma in a variety of ways.
 ...
PMID:Hepatitis B virus X antigen in the pathogenesis of chronic infections and the development of hepatocellular carcinoma. 909 70

The hepatitis B virus X protein plays an important role in the regulation of viral genome expression and has also been implicated in the development of liver cancer associated with chronic viral infection. Several effects have been attributed to X but their biological relevance remains elusive. One of the confusing issues has been so far the uncertainty concerning its cellular location. To gain insight into the mechanism(s) how X exerts its effects, we have analysed its subcellular distribution and its dependency on the cell cycle. We used two complementary approaches namely, immunolocalization using a cell line stably expressing X, and characterization of the dynamics of X location in living cells by means of the reporter gene GFP. Our data clearly define the cytosol as the prime location of X, irrespectively of the cell cycle and show in addition the close attachment of a fraction of X to the nuclear membrane. However, X does not associate with any cytoplasmic vesicles and organelles so far tested. In contrast, our study provides strong evidence for the codistribution of X with the cytosolic fraction of proteasomes. In pulse-chase experiments, X decayed with a half-life of less than 30 min and proteasome-inhibitors did not modify its turnover, suggesting that X colocalization with the proteasome does not simply point to its degradation pathway. The proteolytic processing of the p105 precursor of the p50 subunit of the NF-kappaB transcription factor, which has been shown to be proteasome-dependent, is markedly slow down in the presence of X. These findings suggest that X modulates the processing rate of p105 by acting presumably at the level of the proteasome. Thus, targeting of proteasomes by X might be one of the pathways employed by this viral protein to subvert cellular functions.
 ...
PMID:Cytosol is the prime compartment of hepatitis B virus X protein where it colocalizes with the proteasome. 957 86

Classical antigen presentation by major histocompatibility complex class I molecules involves cytosolic processing of endogenously synthesized antigens by proteasomes and translocation of processed peptides into the endoplasmic reticulum (ER) by transporters associated with antigen presentation (TAP). Alternative pathways for processing of endogenous antigens, generally involving the ER, have been suggested but not fully proved. We analyzed the potential for class I presentation of proteolytic maturation of secretory antigens in the exocytic pathway. We found that hepatitis B (HB) virus secretory core protein HBe can efficiently deliver COOH-terminally located antigenic peptides for endogenous class I loading in the absence of TAP. Antigen presentation to specific cytotoxic T lymphocytes correlates with protein maturation at the COOH terminus, since modification of maturation and transport of HBe through the secretory pathway alters antigen presentation. Both maturation and a necessary processing step occur in the Golgi or post-Golgi compartment. Antigen presentation is independent of proteasome activity, but inhibitors of the trans-Golgi network resident protease furin inhibit both HBe maturation and antigen presentation. These results define a new antigen processing pathway located in the secretory route, with a central role for proteolytic maturation mediated by the subtilisin protease family member furin as an efficient source for antigen presentation.
 ...
PMID:Major histocompatibility complex class I viral antigen processing in the secretory pathway defined by the trans-Golgi network protease furin. 974 29

The hepatitis B virus X protein (HBX) is essential for the establishment of HBV infection in vivo and exerts a pleiotropic effect on diverse cellular functions. The yeast two-hybrid system had indicated that HBX could interact with two subunits of the 26S proteasome. Here we demonstrate an association in vivo of HBX with the 26S proteasome complex by coimmunoprecipitation and colocalization upon sucrose gradient centrifugation. Expression of HBX in HepG2 cells caused a modest decrease in the proteasome's chymotrypsin- and trypsin-like activities and in hydrolysis of ubiquitinated lysozyme, suggesting that HBX functions as an inhibitor of proteasome. In these cells, HBX is degraded with a half-life of 30 min. Proteasome inhibitors retarded this rapid degradation and caused a marked increase in the level of HBX and an accumulation of HBX in polyubiquitinated form. Thus, the low intracellular level of HBX is due to rapid proteolysis by the ubiquitin-proteasome pathway. Surprisingly, the proteasome inhibitors blocked the transactivation by HBX, and this effect was not a result of a squelching phenomenon due to HBX accumulation. Therefore, proteasome function is possibly required for the transactivation function of HBX. The inhibition of protein breakdown by proteasomes may account for the multiple actions of HBX and may be an important feature of HBV infection, possibly in helping stabilize viral gene products and suppressing antigen presentation.
 ...
PMID:Hepatitis B virus X protein is both a substrate and a potential inhibitor of the proteasome complex. 1043 10

Interferon (IFN)-gamma-induced cells express the proteasome subunits low molecular weight protein (LMP)2, LMP7, and MECL-1 (multicatalytic endopeptidase complex-like 1), leading to the formation of immunoproteasomes. Although these subunits are thought to optimize MHC class I antigen processing, the extent of their role and the mechanistic aspects involved remain unclear. Herein, we study the proteolytic generation of an human histocompatibility leukocyte antigen (HLA)-Aw68-restricted hepatitis B virus core antigen (HBcAg) cytotoxic T lymphocyte (CTL) epitope that is recognized by peripheral blood lymphocytes from patients with acute self-limited but not chronic hepatitis B virus (HBV). Immunological data suggest that IFN-gamma-induced rather than uninduced HeLa cells process and present the HBV CTL epitope upon infection with HBcAg-expressing vaccinia viruses. Analyses of 20S proteasome digests of synthetic polypeptides covering the antigenic HBcAg peptide demonstrate that only immunoproteasomes efficiently perform the cleavages needed for the liberation of this HBV CTL epitope. Although the concerted presence of the three immunosubunits appears essential, we find that both catalytically active LMP7 and inactive LMP7 T1A support CTL epitope generation. We conclude that LMP7 influences the structural features of 20S proteasomes, thereby enhancing the activity of the LMP2 and MECL-1 catalytic sites, which provide cleavage specificity. Thus, LMP7 incorporation is of greater functional importance for the generation of an HBV CTL epitope than cleavage specificity.
 ...
PMID:Efficient generation of a hepatitis B virus cytotoxic T lymphocyte epitope requires the structural features of immunoproteasomes. 1066 96

Hepatitis B virus (HBV) has a unique fourth open reading frame coding for a 16.5-kDa protein known as hepatitis B virus X protein (HBX). The importance of HBX in the life cycle of HBV has been well established, but the underlying molecular function of HBX remains controversial. We previously identified a proteasome subunit PSMA7 that interacts specifically with HBX in the Saccharomyces cerevisiae two-hybrid system. Here we demonstrate that PSMC1, an ATPase-like subunit of the 19 S proteasome component, also interacts with HBX and PSMA7. Analysis of the interacting domains among PSMA7, PSMC1, and HBX by deletion and site-directed mutagenesis suggested a mutually competitive structural relationship among these polypeptides. The competitive nature of these interactions is further demonstrated using a modified yeast two-hybrid dissociator system. The crucial HBX sequences involved in interaction with PSMA7 and PSMC1 are important for its function as a transcriptional coactivator. HBX, while functioning as a coactivator of AP-1 and acidic activator VP-16 in mammalian cells, had no effect on the transactivation function of their functional orthologs GCN4 and Gal4 in yeast. Overexpression of PSMC1 seemed to suppress the expression of various reporters in mammalian cells; this effect, however, was overcome by coexpression of HBX. In addition, HBX expression inhibited the cellular turnover of c-Jun and ubiquitin-Arg-beta-galactosidase, two well known substrates of the ubiquitin-proteasome pathway. Thus, interaction of HBX with the proteasome complex in metazoan cells may underlie the functional basis of proteasome as a cellular target of HBX.
 ...
PMID:Structural and functional characterization of interaction between hepatitis B virus X protein and the proteasome complex. 1074 18

Antigenic peptides derived from viral proteins by multiple proteolytic cleavages are bound by MHC class I molecules and recognized by CTL. Processing predominantly takes place in the cytosol of infected cells by the action of proteasomes. To identify other proteases involved in the endogenous generation of viral epitopes, specifically those derived from proteins routed to the secretory pathway, we investigated presentation of the HIV-1 ENV 10-mer epitope 318RGPGRAFVTI327 (p18) to specific CTL in the presence of diverse protease inhibitors. Both metalloproteinase and proteasome inhibitors decreased CTL recognition of the p18 epitope expressed from either native gp160 or from a chimera based on the hepatitis B virus secretory core protein as carrier protein. Processing of this epitope from both native ENV and the hepatitis B virus secretory core chimeric protein appeared to proceed by a TAP-dependent pathway that involved sequential cleavage by proteasomes and metallo-endopeptidases; however, other protease activities could replace the function of the lactacystin-sensitive proteasomes. By contrast, in a second TAP-independent pathway we detected no contribution of metallopeptidases for processing the ENV epitope from the chimeric protein. These results show that, in the classical TAP-dependent MHC class I pathway, endogenous Ag processing of viral proteins to yield the p18 10-mer epitope requires metallo-endopeptidases in addition to proteasomes.
 ...
PMID:Sequential cleavage by metallopeptidases and proteasomes is involved in processing HIV-1 ENV epitope for endogenous MHC class I antigen presentation. 1079 63


1 2 3 4 5 6 7 8 9 Next >>