Dismantle microtubule networks

ICP0 co-localizes with α-tubulin, and dismantles host cell microtubule networks once it translocates to the cytoplasm.^[9]

Transcription

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.^[10]

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 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.^[11][12] 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.^[13] Barriers to viral replication induced by interferons can also be overcome by the action of ICP0.^[14] 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.^[15]

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

Small ubiquitin-related modifier 1 (SUMO-1) is a protein produced by human cells that is involved in the modification of many proteins, including human PML protein.^[16][17][18] HSV-1 ICP0 and several of its homologs in other herpes viruses bind to SUMO-1 in a manner similar to endogenous proteins,^[19] causing depletion of SUMO-1, and disruption of nuclear bodies.^{[2][20][21][22][23][24]}

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)^[25][26] 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.^[27] This interaction is attributed to the partial similarity of ICP0 to the human protein CoREST, also called REST corepressor 1 (RCOR1),^[3] which combines with NRSF to repress expression of neuronal genes in non-neuronal cells.^[27][28]

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.^[29] 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.^[4] The repressed production of immediate-early HSV genes may contribute to the establishment of latency during infection with herpes viruses.^[4]

CoREST and NRSF combine with another cellular protein, histone deacetylase-1 (HDAC) to form a HDAC/CoREST/NRSF complex. This complex silences production of the HSV-1 protein ICP4 by interfering with chromatin remodeling of the viral DNA that is necessary to allow viral gene transcription; it deacetylates histones associated with viral DNA in viral chromatin.^[4] Furthermore, an NRSF-binding region is located between the viral genes expressing proteins ICP4 and ICP22.^[4] 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.^[3][25]

Interaction with latency-associated RNA transcript (LAT)

During latent infection a viral RNA transcript inhibits expression of the herpes virus ICP0 gene via an antisense RNA mechanism.^[30] The RNA transcript is produced by the virus and accumulates in host cells during latent infection; it is known as Latency Associated Transcript (LAT).^[30] A chromatin insulator region between promoters of the LAT and ICP0 genes of the HSV-1 genome may allow for the independent regulation of their expression.^[31]

Silencing of ICP0 gene activity by ICP4

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.^[32] The balance between ICP0 and ICP4 dictates whether the ICP0 gene can be efficiently transcribed.^[32]