Жұқпалы герпес вирусының ICP0 протеині: құрылымы, функциясы және вирустық инфекциядағы ролі

Protein

Human Herpes Virus (HHV) Infected Cell Polypeptide 0 (ICP0) is a protein, encoded by the DNA of herpes viruses. It is produced by herpes viruses during the earliest stage of infection, when the virus has recently entered the host cell; this stage is known as the immediate early or α ("alpha") phase of viral gene expression. During these early stages of infection, ICP0 protein is synthesized and transported to the nucleus of the infected host cell. Here, ICP0 promotes transcription from viral genes, disrupts structures in the nucleus known as nuclear dots or promyelocytic leukemia (PML) nuclear bodies,

ICP0 was identified as an immediate early polypeptide product of Herpes simplex virus 1 (HSV 1) infection in 1976. The 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 in 1986. This sequence predicted a 775 amino acid sequence with a molecular weight of 78.5 KDa. At the time of gene isolation, ICP0 was known as IE110 as gel electrophoresis experiments performed prior to obtaining the gene sequence indicated the ICP0 protein weighed 110 kDa. Post translational modifications, such as phosphorylation or sumoylation, were presumed to account for the actual protein size appearing 30 kDa larger than that of the predicted amino acid sequence.

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

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

ICP0 is responsible for overcoming a variety of cellular antiviral responses. After translocating to the nucleus early in infection, ICP0 promotes the 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) and IRF7, which are key transcription factors that induce production of antiviral cytokines called interferons. Barriers to viral replication induced by interferons can also be overcome by the action of ICP0. This function of ICP0 also prevents the production of RNase L, an enzyme that degrades single stranded viral and cellular RNAs and induces host cell apoptosis in virus infected cells.

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 neuronal or non neuronal origin; NRSF is found in non neuronal cells but not in fully differentiated neurons. 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 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 during infection with herpes viruses.

During latent infection a viral RNA 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).

Although it is tempting to hypothesize that LAT is the repressor of the ICP0 gene, evidence supporting this hypothesis is lacking. Recent data suggest that ICP4 strongly suppresses the ICP0 gene, and ICP0 antagonizes ICP4. The balance between ICP0 and ICP4 dictates whether the ICP0 gene can be efficiently transcribed. Simian varicella virus (SVV) is a varicellovirus that, like HSV 1 and HSV 2, belongs 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 (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 ICP 0 homologs and nomenclature Herpes virus ICP0 Synonyms Structural homology and functional similarity HHV 1 Herpes simplex virus 1 (HSV 1) ICP0, IE110 (n/a) HHV 2 Herpes simplex virus 2 (HSV 2) has 61.5% amino acid sequence homology to HSV 1 ICP0. HHV 4 Epstein Barr virus (EBV), lymphocryptovirus BZLF1 Analogous to ICP0 and VZV ORF 61, BZLF1 is modified by SUMO 1 and disrupts PML Nuclear Bodies. HHV 5 Cytomegalovirus (CMV) IE1, IE72 Disrupts PML bodies in a manner similar to ICP0.