HHV Infected Cell Polypeptide 0 (ICP0)

Human Herpes Virus Infected Cell Polypeptide 0 (ICP0) is a protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

, encoded by the DNA

DNA

Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

of herpes virus

Herpesviridae

The Herpesviridae are a large family of DNA viruses that cause diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word herpein , referring to the latent, recurring infections typical of this group of viruses...

es. It is produced by herpes viruses during the earliest stage of infection, when the virus has recently entered the host cell

Cell (biology)

The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

; this stage is known as the immediate-early
Immediate early gene
Immediate early genes are genes which are activated transiently and rapidly in response to a wide variety of cellular stimuli. They represent a standing response mechanism that is activated at the transcription level in the first round of response to stimuli, before any new proteins are synthesized...

or α ("alpha") phase of viral gene expression. During these early stages of infection, ICP0 protein is synthesized and transported to the nucleus

Cell nucleus

In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...

of the infected host cell. Here, ICP0 promotes transcription

Transcription (genetics)

Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...

from viral gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

s, disrupts structures in the nucleus known as nuclear dots

Nuclear dots

Nuclear dots are punctate structures found in the nucleus of certain cells. Nuclear bodies were first seen as prominent interchromatin structures in the nuclei of malignant or hyperstimulated animal cells...

or promyelocytic leukemia (PML) nuclear bodies, and alters the expression of host and viral genes in combination with a neuron

Neuron

A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

specific protein. At later stages of cellular infection, ICP0 relocates to the cell cytoplasm

Cytoplasm

The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

to be incorporated into new virion particles.

History and background

ICP0 was identified as an immediate-early polypeptide product of Herpes simplex virus-1 (HSV-1)

Herpes simplex virus

Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...

infection in 1976. The gene

Gene

, in HSV-1, from which ICP0 is produced is known as HSV-1 α0 ("alpha zero") , Immediate Early (IE) gene 1, or simply as the HSV-1 ICP0 gene. The HSV-1 ICP0 gene was characterized and sequenced

DNA sequencing

DNA sequencing includes several methods and technologies that are used for determining the order of the nucleotide bases—adenine, guanine, cytosine, and thymine—in a molecule of DNA....

in 1986. This sequence predicted a 775 amino acid

Amino acid

Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

sequence with a molecular weight of 78.5 KDa

Atomic mass unit

The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...

. At the time of gene isolation, ICP0 was known as IE110 as gel electrophoresis

Gel electrophoresis

Gel electrophoresis is a method used in clinical chemistry to separate proteins by charge and or size and in biochemistry and molecular biology to separate a mixed population of DNA and RNA fragments by length, to estimate the size of DNA and RNA fragments or to separate proteins by charge...

experiments performed prior to obtaining the gene sequence indicated the ICP0 protein weighed 110 kDa. Post-translational modifications, such as phosphorylation

Phosphorylation

Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

or sumoylation, were presumed to account for the actual protein size appearing 30 kDa larger than that of the predicted amino acid sequence.

Dismantle microtubule networks

ICP0 co-localizes with α-tubulin, and dismantles host cell microtubule networks once it translocates to the cytoplasm.

Transcription

In HSV-1 infected cells, ICP0 activates transcription of many viral and cellular genes. It acts synergistically HSV-1 immediate early (IE) protein, ICP4, and is essential for reactivation of latent herpes virus and viral replication.

Degradation of antiviral pathways

ICP0 is responsible for overcoming a variety of cellular antiviral responses. After translocating to the nucleus early in infection, ICP0 promotes degradation of many cellular antiviral genes, including those for nuclear body-associated proteins promyelocytic leukemia protein (PML) and Sp100, causing disruption of PML nuclear bodies and reduced cellular antiviral capacity. ICP0 also inhibits the activity of IFN regulatory factors (IRF3

IRF3

Interferon regulatory factor 3, also known as IRF3, is an interferon regulatory factor.- Function :IRF3 is a member of the interferon regulatory transcription factor family. IRF3 was originally discovered as a homolog of IRF1 and IRF2...

) and IRF7

IRF7

Interferon regulatory factor 7, also known as IRF7, is a member of the interferon regulatory factor family of transcription factors.-Further reading:- External links :...

, which are key transcription factor

Transcription factor

In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

s that induce production of antiviral cytokine

Cytokine

Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s called interferon

Interferon

Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...

s.
Barriers to viral replication induced by interferons can also be overcome by the action of ICP0. This function of ICP0 also prevents production of RNase L

RNAse L

RNase L is an interferon-induced ribonuclease which, upon activation, destroys all RNA within the cell .- Production and Activation :...

, an enzyme that degrades single-stranded viral and cellular RNAs and induces host cell apoptosis

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

in virus infected cells.

Interaction with host cell SUMO-1 protein and disruption PML Nuclear Bodies

Small ubiquitin-related modifier 1

Small ubiquitin-related modifier 1 is a protein that in humans is encoded by the SUMO1 gene.Most cleft genes have a sumoylation component .-Interactions:...

(SUMO-1) is a protein produced by human cells that is involved in the modification of many proteins, including human PML protein.
HSV-1 ICP0 and several of its homologs in other herpes viruses bind to SUMO-1 in a manner similar to endogenous proteins, causing depletion of SUMO-1, and disruption of nuclear bodies.

Interaction with neuron-differentiating protein NRSF and protein cofactor coREST

ICP0 interacts with a human protein, known as Neuronal Restrictive Silencer Factor (NRSF) or RE1-silencing transcription factor (REST) that regulates differences in gene expression between cells of neuron

Neuron

al or non-neuronal origin; NRSF is found in non-neuronal cells but not in fully differentiated neurons. This interaction is attributed to the partial similarity of ICP0 to the human protein CoREST, also called REST corepressor 1 (RCOR1

RCOR1

REST corepressor 1 is a protein that in humans is encoded by the RCOR1 gene.-Interactions:RCOR1 has been shown to interact with HMG20B, HDAC1, Histone deacetylase 2, RE1-silencing transcription factor and PHF21A.-Further reading:...

), which combines with NRSF to repress expression of neuronal genes in non-neuronal cells.

Although the full NRSF protein is not typically found in neurons, truncated forms of NRSF are produced that selectively control the expression of certain neurotransmitter

Neurotransmitter

Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

channels in specialized neurons. Combination of ICP0 with these NRSF-like neuronal factors may silence herpes genes in neurons, blocking the production of other immediate-early genes such as ICP4 and reducing production of ICP22. The repressed production of immediate-early HSV genes may contribute to the establishment of latency

Virus latency

Virus latency is the ability of a pathogenic virus to lie dormant within a cell, denoted as the lysogenic part of the viral life cycle. A latent viral infection is a type of persistent viral infection which is distinguished from a chronic viral infection...

during infection with herpes viruses.

CoREST and NRSF combine with another cellular protein, histone deacetylase-1 (HDAC)

Histone deacetylase

Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...

to form a HDAC/CoREST/NRSF complex. This complex silences production of the HSV-1 protein ICP4 by interfering with chromatin remodeling

Chromatin remodeling

Chromatin remodeling is the enzyme-assisted movement of nucleosomes on DNA.This is performed by chromatin remodeling complexes like SWI/SNF , RSC and Imitation SWI complexes ....

of the viral DNA that is necessary to allow viral gene transcription

Transcription (genetics)

; it deacetylates

Histone acetylation and deacetylation

In histone acetylation and deacetylation, the histones are acetylated and deacetylated on lysine residues in the N-terminal tail and on the surface of the nucleosome core as part of gene regulation. These reactions are typically catalyzed by enzymes with "histone acetyltransferase" or "histone...

histones associated with viral DNA in viral chromatin

Chromatin

Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...

. Furthermore, an NRSF-binding region is located between the viral genes expressing proteins ICP4 and ICP22. ICP0 interacts with coREST, dissociating HDAC1 from CoREST/NRSF in the HDAC/CoREST/NRSF complex and preventing the silencing of the HSV genome in non-neuronal cells.

Interaction with latency-associated RNA transcript (LAT)

During latent infection a viral RNA

RNA

Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

transcript inhibits expression of the herpes virus ICP0 gene via an antisense RNA mechanism. The RNA transcript is produced by the virus and accumulates in host cells during latent infection; it is known as Latency Associated Transcript (LAT). A chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...

insulator region between promoters of the LAT and ICP0 genes of the HSV-1 genome may allow for the independent regulation of their expression.

Silencing of ICP0 gene activity by ICP4

Although it is tempted to hypothesize that LAT is the repressor of ICP0 gene, evidences supporting this hypothesis has been lacking. Recent data suggest that ICP4 strongly suppresses ICP0 gene, and ICP0 antagonizes ICP4. The balance between ICP0 and ICP4 dictates if ICP0 gene could be efficiently transcribed.

Homologs across Herpes virus species

The ICP0 gene and protein from HSV-1 have orthologs in related viruses from the herpes virus family. HSV-2 ICP0 is predicted to produce a polypeptide of 825 amino acids with a predicted molecular weight of 81986 Da, and 61.5% amino acid sequence similarity to HSV-1 ICP0. Simian varicella virus

Simian varicella virus

The Simian Varicella Virus or SVV infects primates and shares clinical, pathological, immunological, and virological features with varicella-zoster virus infection of humans. Monkeys that had been inoculated intratracheally with SVV developed diffuse varicella 10 to 12 days later...

(SVV) is a varicellovirus

Varicellovirus

Varicellovirus is a genus of Alphaherpesvirinae.The varicellovirus genus contains several closely related viruses, including Varicella zoster virus , the causative agent of chickenpox in humans, and Pseudorabies virus , the causative agent of Aujeszky's disease.- Morphology :As with other...

that, like HSV-1 and HSV-2, belongs to the alphaherpesvirinae

Alphaherpesvirinae

Alphaherpesvirinae is a subfamily of Herpesviridae primarily distinguished by reproducing more quickly than other subfamilies of Herpesviridae. In animal virology the most important herpesviruses belong to the Alphaherpesvirinae...

subfamily of herpes viruses. SVV expresses an HSV-1 LAT ortholog known as SVV LAT, and an HSV-1 ICP0 ortholog known as SVV ORF-61 (Open Reading Frame 61). Varicella Zoster Virus

Varicella zoster virus

Varicella zoster virus is one of eight herpes viruses known to infect humans . It commonly causes chicken-pox in children and Herpes zoster in adults and rarely in children.-Nomenclature:...

(VZV) is another varicellovirus in which a homolog of HSV-1 ICP0 gene has been identified; VSV ORF-61 is a partial homolog and a functional replacement for HSV-1 ICP0 gene.

Herpes virus		ICP0 Synonyms	Structural homology and functional similarity
Herpes virus ICP-0 homologs and nomenclature
HHV-1	Herpes simplex virus Herpes simplex virus Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious... -1 (HSV-1)	ICP0, IE110	(n/a)
HHV-2	Herpes simplex virus-2 (HSV-2)	ICP0, IE110	has 61.5% amino acid Amino acid Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen... sequence homology to HSV-1 ICP0.
HHV-3	Varicella zoster virus Varicella zoster virus Varicella zoster virus is one of eight herpes viruses known to infect humans . It commonly causes chicken-pox in children and Herpes zoster in adults and rarely in children.-Nomenclature:... (VZV)	ORF-61	Shows homology to HSV-1 in the cysteine Cysteine Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid... rich RING finger domain RING finger domain In molecular biology, a RING finger domain is a protein structural domain of zinc finger type which contains a Cys3HisCys4 amino acid motif which binds two zinc cations. This protein domain contains from 40 to 60 amino acids... found at the N-terminal end of ORF-61. Two cell lines expressing VZV ORF-61 are specifically able to support infection by synthetic HSV with ICP0-deletion.
SVV	Simian varicella virus Simian varicella virus The Simian Varicella Virus or SVV infects primates and shares clinical, pathological, immunological, and virological features with varicella-zoster virus infection of humans. Monkeys that had been inoculated intratracheally with SVV developed diffuse varicella 10 to 12 days later...	ORF-61	The mRNA for ORF-61 contains sequence that is antisense to SVV LAT, allowing for gene silencing of ORF-61 by SVV LAT in an analogous mechanism to ICP0 silencing by LAT in HSV-1.
PRV	Pseudorabies Pseudorabies Pseudorabies is a viral disease in swine that is endemic in most parts of the world. It is caused by Suid herpesvirus 1 , which is also called Pseudorabies virus and is also known as Aujeszky's disease, and in cattle as mad itch. PRV is considered to be the most economically important viral... virus	EP0	Both HSV-1 ICP0 and VZV ORF-61 support growth and infectability of PRV that is deficient in its ICP0 ortholog, EP0.
HHV-4	Epstein-Barr virus Epstein-Barr virus The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis... (EBV), lymphocryptovirus	BZLF1	Analogous to ICP0 and VZV ORF-61, BZLF1 is modified by SUMO-1 and disrupts PML Nuclear Bodies Nuclear dots Nuclear dots are punctate structures found in the nucleus of certain cells. Nuclear bodies were first seen as prominent interchromatin structures in the nuclei of malignant or hyperstimulated animal cells... .
HHV-5	Cytomegalovirus Cytomegalovirus Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses... (CMV)	IE1, IE72	Disrupts PML bodies in a manner similar to ICP0.

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