![HBV Genome](https://upload.wikimedia.org/wikipedia/commons/0/00/HBV_Genome.svg)
HBx is a
hepatitis B
Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.
Many people have no symptoms during an initial infection. Fo ...
viral protein
A viral protein is both a component and a product of a virus. Viral proteins are grouped according to their functions, and groups of viral proteins include structural proteins, nonstructural proteins, regulatory proteins, and accessory proteins. Vi ...
.
It is 154
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s long and interferes with transcription, signal transduction,
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
progress, protein degradation,
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
and chromosomal stability in the host. It forms a heterodimeric complex with its cellular target protein (HBX interacting protein:
HBXIP
Hepatitis B virus X-interacting protein is a protein that in humans is encoded by the ''HBXIP'' gene.
This gene encodes a protein that specifically complexes with the C-terminus of hepatitis B virus X protein (HBx). The function of this protein i ...
), and this interaction dysregulates
centrosome
In cell biology, the centrosome (Latin centrum 'center' + Greek sōma 'body') (archaically cytocentre) is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle progres ...
dynamics and
mitotic spindle
In cell biology, the spindle apparatus refers to the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a pr ...
formation. It interacts with
DDB1
DNA damage-binding protein 1 is a protein that in humans is encoded by the ''DDB1'' gene.
Gene
The gene's position is on chromosome 11q12-q13.
Protein
The DDB1 gene encodes the large subunit of DNA damage-binding protein, a heterodimer composed ...
(Damaged DNA Binding Protein 1) redirecting the
ubiquitin ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
activity of the
CUL4-DDB1
E3 complexes, which are intimately involved in the intracellular regulation of
DNA replication and repair,
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
and signal transduction.
Although Protein X is normally absent in the
Avihepadnavirus
''Avihepadnavirus'' is a genus of viruses, in the family ''Hepadnaviridae''. Birds serve as natural hosts. There are three species in this genus. Diseases associated with this genus include: hepatitis, hepatocellular carcinomas (chronic infectio ...
, a vestigial version has been identified in the duck hepatitis virus genome.
Although it lacks significant sequence identity with any known vertebrate proteins, it seems likely that it evolved from a
DNA glycosylase
DNA glycosylases are a family of enzymes involved in base excision repair, classified under EC number EC 3.2.2. Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. DNA glycosylases catalyze the first st ...
.
Transgenic mice expressing the X protein in liver are more likely than the wild type to develop hepatocellular carcinoma. This is because the X protein promotes cell cycle progression while binding to and inhibiting tumor suppressor protein p53 from performing their role. Experimental observations also suggest that HBx protein increases
TERT
Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.
T ...
and
telomerase
Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most euka ...
activity, prolonging the lifespan of hepatocytes and contributing to malignant transformation.
Molecular effects of HBx
HBx causes many cellular alterations. These alterations are due to direct actions of HBx and indirect actions due to large increases in
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(ROS) partly induced by HBx. HBx appears to dysregulate a number of cellular pathways. HBx causes dysregulation by binding to genomic DNA, changing expression patterns of miRNAs, affecting histone methyltransferases, binding to
SIRT1
Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.
SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (''S. cerevisiae''), referring to the fact t ...
protein to activate transcription, and cooperating with histone methylases and demethylases to change cell expression patterns.
HBx is partly responsible for the approximate 10,000-fold increase in intracellular ROS upon chronic HBV infection.
HBx can localize to the mitochondria where HBx decreases the mitochondrial membrane potential and causes increased release of ROS.
In addition, other HBV proteins,
HBsAg
HBsAg (also known as the Australia antigen) is the surface antigen of the hepatitis B virus (HBV). Its presence in blood indicates current hepatitis B infection.
Structure and function
The viral envelope of an enveloped virus has different sur ...
and
HBcAg
HBcAg (core antigen) is a hepatitis B viral protein. It is an indicator of active viral replication; this means the person infected with Hepatitis B can likely transmit the virus on to another person (i.e. the person is infectious).
Structure ...
,
also increase ROS through interactions with the
endoplasmic reticulum
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
. ROS cause more than 20 types of DNA damage.
Oxidative DNA damage is mutagenic.
HBx has large effects on the transcription levels of many genes. In a transgenic mouse model expressing the HBx gene of hepatitis B virus (but not other HBV genes), most mice developed hepatic tumors.
In these HBx transgenic mice there were 10,553 differentially
DNA methylated regions (6,668 hypermethylated and 3,885 hypomethylated regions). In mammalian cells, large clusters of CpG dinucleotides known as
CpG islands
The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...
(CGIs) appear to act as key
epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
elements regulating gene expression.
Hyper-methylation of the CGIs in promoters can silence genes, while hypo-methylation of CGIs within distal
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
s of genes can also repress transcription of genes.
A large proportion of the methylation alterations in the HBx transgenic mice were at CGIs. HBx especially induced hypo-methylation of distal intragenic CGIs required for active expression. There were 647 genes containing intragenic CGIs that were hypo-methylated in HBx transgenic mouse liver.
HBx also directly interacts with many genes. Several thousand protein-coding genes appear to have HBx-binding sites.
In addition to binding to protein coding genes, HBx bound to the promoters controlling 15
microRNA
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...
s and 16
Long non-coding RNA
Long non-coding RNAs (long ncRNAs, lncRNA) are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein. This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as mic ...
s.
For the 15 miRNAs with promoters bound by HBx, expression levels increased for eight, decreased for 5, and did not change significantly for two. Each microRNA with altered level of expression can affect the expression of several hundred messenger RNAs (see
microRNA
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...
).
In addition to its effects on transcription levels of host genes, HBx seams to affect the in-vivo synthesis of pgRNA in HBV replicating cells. As HBx is recruited on
cccDNA
cccDNA (covalently closed circular DNA) is a special DNA structure that arises during the propagation of some viruses in the cell nucleus and may remain permanently there. It is a double-stranded DNA that originates in a linear form that is lig ...
, it decreases levels of histone acetylation by decreasing recruitment
p300 acetylases and increasing recruitment of hSirtl and
HDAC1
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the ''HDAC1'' gene.
Function
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. T ...
deacetylases. This, in turn, decreases heterochromatinization of HBV minichromosome, and increases the production of pgRNA. In cells infected by HBx defective mutants, levels of cccDNA remain unchanged, while there is a decrease in pgRNA transcription. Introduction of nucleus localized HBx protein seams to restore viral replication to cells infected by HBx-deficient virus.
Relation to PRMT1
In a study purifying cancerous liver cells infected with HBV, the level of
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
of protein arginine methyltransferase 1 (
PRMT1
Protein arginine N-methyltransferase 1 is an enzyme that in humans is encoded by the ''PRMT1'' gene. The HRMT1L2 gene encodes a protein arginine methyltransferase that functions as a histone methyltransferase specific for histone H4.
Function
...
) was found to be associated with changes in transcription due to the
methyltransferase
Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossm ...
function of PRMT1. Overexpression causes a reduction in the number of HBV genes transcribed, while conversely, underexpression causes an increase. PRMT1 was also found to be recruited by HBV DNA during the replication process to regulate the transcription process. Increased HBx expression in turn leads to an inhibition of PRMT1-mediated protein
methylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
, benefiting viral replication.
References
{{Viral proteins
Viral nonstructural proteins
Hepatitis B virus