Multifunctional protein that may modulate protein degradation pathways, apoptosis, transcription, signal transduction, cell cycle progress, and genetic stability by directly or indirectly interacting with host factors. Cd4 receptors help white blood cells to communicate with other cells of the immune system when producing an immune response. Hbv particles were produced in culture medium of hepg2 cells transfected with the mammalian expression vector containing the linear hbv genome, as assessed by commercially available elisa assay. Hepatitis b virus wholex and x protein play distinct roles. Hepatitis b virus, abbreviated hbv, is a partially doublestranded dna virus, a species of the genus orthohepadnavirus and a member of the hepadnaviridae family of. Hepatitis b virus x protein inhibits transforming growth. Although not binding directly to dna, hbx can transactivate transcription through multiple cisacting elements including ap1, ap2, atfcreb, nf. Hbx is an essential viral regulatory protein that has pleomorphic effects within the. Hbeag is dispensable for in vivo infections 28, 33. Hepatitis b virus hbv x protein hbx activated the serum response element. Structural and functional analyses of hepatitis b virus x. Hbv replicates through an rna intermediate and can integrate into the host genome. Contributions from leading researchers examine the cell biology of the liver, the.
Hbx protein is a multifunctional viral regulator that modulates transcription, signaling pathways, protein degradation, and cell responses to genotoxic stress, acting on cell cycle checkpoints, cell death, and carcinogenesis tang et al. Despite the development of vaccines, the hepatitis b virus remains a major cause of human liver disease1. Hepatitis b virus biology microbiology and molecular. Majano p, larapezzi p, lopezcabrera m, apolinario a, morenootero r, garciamenzon c 2001 hepatitis b virus x protein transactivates inducible nitric oxide synthase gene promoter through the proximal nuclear factor kappabbinding site. Biology and pathobiology remains a definitive volume in the field of hepatology, relating advances in biomedical sciences and engineering to understanding of liver structure, function, and disease. The capsid of the hepatitis b virus has a very unique structure. The hepatitis b virus is an important cause of acute and chronic liver disease. Hepatitis b virus x protein induces hepatic steatosis by. 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. Among hepatitis b viral proteins, hbx protein functions as a multifunctional. Hepatitis b virus belongs to the hepadnavirus family of double stranded dna viruses see below hepatitis c virus is a flavivirus, a single stand rna virus hepatitis d which is also known as delta agent is a circular rna that is more similar to a plant viroid than a complete virus.
To isolate cellular proteins interacting with hepatitis b virus x protein hbx, from hepg2 cells infected with hepatitis b virus hbv. Bridging the gap between basic scientific advances and the understanding of liver disease the extensively revised new edition of the premier text in the field. It consists of small s, medium m and large l protein. Hepatitis b virus x proteinelevated msl2 modulates hepatitis. It comprises 452 nucleotides that encode a 154amino acid regulatory protein with a molecular mass of 17 kda. However, its potential effect on the progression of hepatocellular carcinoma remains yet unclear. Over 250 million people are infected chronically with hepatitis b virus. Two additional gene products expressed during natural infections are of unknown function, hepatitis x protein hbx and hepatitis eantigen hbeag. Aug 16, 2012 hepatitis b virus x protein hbx has been shown to be responsible for the development of hepatocellular carcinoma hcc caused by hepatitis b virus infection. Role of hepatitis b virus x protein in regulating lim and sh3. Hbv, a member of the hepadnaviridae family, is a small dna virus with unusual features similar to retroviruses. A liverspecific bile acid transporter named the sodium taurocholate cotransporting polypeptide ntcp has been identified as the cellular receptor for hbv and its satellite, the hepatitis d virus hdv.
The core protein, also known as the core antigen, is an important serologic marker for hbv infection. The enhi and x promoter are enhanced by hbx as well, suggesting that hbx is under autoregulation. Hepatitis b virus x protein hbx binds antiapoptotic bclxl through its bh3like motif to promote viral replication. May be directly involved in development of cirrhosis and liver cancer hepatocellular carcinoma. In part, this is the parsimony of viruses, where a minimal number of proteins perform a wide variety of functions. Xorf is transcribed independently under the control of enhi and x promoter and encodes for a 154 aminoacidlong peptide called hepatitis b virus x protein hbx, with a molecular mass of. Viral evolution, morphology, and classification biology 2e. Hepatitis delta virus hdv is a naturally occurring satellite of hepatitis b virus hbv. Hepatitis b virus biology microbiology and molecular biology. Visualization of a 4helix bundle in the hepatitis b virus. A cdna library was made from these cells exposed to hbv. The hepatitis c virus hcv is a significant human pathogen of global impact. It is composed of many monomers which interact to provide flexibility to its structure and function.
Tiollais p, charnay p, vyas gn 1981 biology of hepatitis b virus. In a transgenic mouse model expressing the hbx gene of hepatitis b virus but not other hbv genes, most mice developed hepatic tumors. Structurefunction relationships and role in viral pathogenesis. The rna is encapsidated by the hepatitis delta antigen, and hdv acts as a parasite on the unrelated hepatitis b virus hbv, using hbv envelopes containing the hepatitis b attachment protein hbsag. Structural biology of the hepatitis c virus proteins. This lesson will describe the structure and function of the virus that causes hepatitis a. X protein x hepatitis b virus genotype a2 subtype adw2. Hbcag hbeag is a splice variant hbcag is the main structural protein of hbv icosahedral nucleocapsid and it has function in replication of the virus. The virus itself is extremely tiny and can get into areas that other viruses cannot infect. It is also the most common form of parenterally transmitted viral hepatitis. The yeast twohybrid system had indicated that hbx could interact with two subunits of the 26s proteasome. The hepatitis b virus pres1 domain hijacks host trafficking. Origin and structure similarity with the central domain of dna glycosylase. Hepatitis b virus hbv infects more than 300 million people worldwide and is a common cause of liver disease and liver cancer.
Hepatitis b virus is one of the smallest human pathogens, encoded by a 3,200bp genome with only four open reading frames. A longitudinal study is available spanning the molecular evolution of hepatitis b virus over 25 years. In these hbx transgenic mice there were 10,553 differentially dna methylated regions 6,668 hypermethylated and 3,885 hypomethylated regions. Transgenic mice expressing the x protein in liver are more likely than the wild type. Hbx activates multiple cytoplasmic signaling pathways see fig. Hepatitis b x protein hbx plays an essential role in the hepatitis b virus hbv replication cycle, but the function of hbx has been elusive until recently. It is 154 amino acids long and interferes with transcription, signal transduction, cell cycle progress, protein degradation, apoptosis and chromosomal stability in the host. The hbx protein of hepatitis b virus has been found to coopt a hostcell enzyme that targets the smc56 protein complex for degradation. Hbx is aptly named as its entire function and cellular localization remain a mystery. During the last decade, efforts have centered on elucidating the oncogenic role of px in hepatitis b virus infection. Structure and functions of hepatitis b virus x protein. Unlike most other viral oncogenes, however, x gene transgenic mouse.
Origin and structure similarity with the central domain of dna glycosylase formijn j. Molecular biology of the hepatitis b virus presents a comprehensive account of the various molecular aspects of the life cycle of the hepatitis b virus hbv. X is required for the establishment of an infection in vivo 32, 254 but is dispensable for virus replication in transfected cells 17, 237. Many people have no symptoms during the initial infection. Hbxip, and this interaction dysregulates centrosome dynamics and mitotic spindle formation. The smallest orf in the hbv genome encodes for the hepatitis b x protein hbx. Hepatitis b virus hbv has been implicated as a potential trigger of hepatic steatosis although molecular mechanisms involved in the pathogenesis of hbvassociated hepatic steatosis. Chronic hepatitis b virus hbv infection is a major risk factor of hcc and is reported to be associated with more than half of hcc cases worldwide 1, 2.
Hepatitis b virus world scientific publishing company. Hbx protein is a multifunctional viral regulator that modulates transcription. Hepatitis b virus x protein an overview sciencedirect topics. The x gene is conserved among mammalian hepadnaviruses and the x protein, px, is essential for viral propagation at least in the woodchuck. Multifunctional protein that plays a role in silencing host antiviral defenses and promoting viral transcription. The hepatitis b x antigen is a 154 amino acid 17 kda multifunctional protein involved in the development of liver chirrosis and hepatocellular carcinoma. Hbsag hepatitis b surface antigen hbsag was the first hepatitis b virus protein to be discovered. Biology and pathobiology remains a definitive volume in the field of hepatology, relating advances in biomedical sciences and engineering to understanding of liver structure, function, and disease pathology and treatment. It likes to attack the liver of the host, specifically going after. Structural and biochemical investigations of the hepadnavirus polymerases have been complicated by the. Hepatitis b hb is an infectious disease caused by the hepatitis b virus hbv that affects the liver. Jul 14, 20 structurebased rational design of peptide inhibitors to disrupt the recognition and interaction between hepatitis b virus large envelope protein and human hepatocyte receptor. Hepatitis b virus hbv infection affects 240 million people worldwide.
Backgrounddiscovery the concept behind modern virology can be traced back to adolf mayer, dimitri ivanofsky and martinus beijerinck who, independently in the late 1880s, discovered what was later to be called tobacco mosaic virus tmv. Hepatitis b virus x protein hbx 1 has been demonstrated to function as a transcriptional transactivator of a variety of viral and cellular promoterenhancer elements 1, 2. Identifying and characterizing interplay between hepatitis b virus x. Synergistic activation of the serum response elementdependent. This figure was used as a prior value for the fixed mean rate of amino acid replacement in protein x of the. Ntcp likely acts as a major determinant for the liver tropism and species specificity of hbv and hdv at the entry level. Hepatitis b virus x protein in the pathogenesis of hepatitis.
The hiv virus binds the cd4 receptor on the surface of human cells. Although this protein is rarely detected in free forms in patients with hbv, the antibody directed against this protein is almost always found in people who. Hbx gene is the smallest of the four partially overlapping open reading frames of hbv. Reprints and eprints sponsored supplements branded books journals career network. After the lesson, there will be a few questions to test what you have learned. Molecular biology of the hepatitis b virus mclachlan, alan on.
Here, the authors provide the structure of the hbx bh3like domain and bclxl. The book covers both the molecular aspects of hepatitis b virus replication and gene expression in vivo and in model systems, and the clinical impact of genetic variants or immunological response in chronic infection. Major emphasis is laid on the molecular mechanisms underlying hepatitis b virusassociated liver carcinogenesis and their. Ioap sciforum preprints scilit sciprofiles mdpi books encyclopedia mdpi blog. Some develop a rapid onset of sickness with vomiting, yellowish skin, tiredness, dark urine and abdominal pain. A, structure of the hepatitis b virus hbv dna genome, showing the four. A protein produced by the hepatitis b virus hbv helps cause human liver cancer by altering the bodys expression of noncoding rnas ncrnas.
Viruses free fulltext comprehensive analysis of hepatitis b. Hbx has large effects on the transcription levels of many genes. It is 154 amino acids long and interferes with transcription. It forms a heterodimeric complex with its cellular target protein hbx interacting protein. Evidence that cytoplasmic location of x protein is essential for gene transactvation. Pdf the hepatitis b virus hbv genome codes for a 16. Hepatitis b virus hbv has a unique fourth open reading frame coding for a 16. The hbx, coded by the hbv x gene, is believed to play a vital role in the pathogenesis of hcc by influencing cell cycle, proliferation, and apoptosis at the levels of cell signaling and transcription 3, 4.
The importance of hbx in the life cycle of hbv has been well established, but the underlying molecular function of hbx remains controversial. Hepatitis b virus x protein is both a substrate and a. The hepatitis b virus hbv c gene encodes the core protein and the precore protein. Structural and functional characterization of interaction. Yet the virus shows a remarkable diversity in structural features, often with the same proteins adopting several conformations. Hepatitis b virus x proteinelevated msl2 modulates hepatitis b virus covalently closed circular dna by inducing degradation of apobec3b to enhance hepatocarcinogenesis yuen gao,1 jinyan feng,1 guang yang,1 shuqin zhang,1 yunxia liu,1 yanan bu,1 mingming sun,1 man zhao,1 fuquan chen,1 weiying zhang,1 lihong ye,2 and xiaodong zhang1. Phosphorylation analysis of hepatitis b virus core protein in. This 154 amino acid protein has conserved sequences between human, woodchuck, and ground squirrel hepadnaviruses.
The evolutionary analysis at issue of x indicates that present. Therapeutic intervention to cure infections, although improving with recent specific antivirals, still remains a challenge because of the diversity of hcv genotypes and the ability of the virus to quickly evolve resistance. Lim and sh3 protein 1 lasp1, a focal adhesion protein, is expressed in an upregulation manner in the hcc tissues. However, it differs from true viruses in that it does not code for its own attachment protein. Hepatitis b virus hbv causes transient and chronic infections of the liver. Molecular mechanism of hepatitis b virus x protein function in.
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