Herpes Simplex Virus Type 1 Immediate-Early Protein ICP22 Is Required for VICE Domain Formation during Productive Viral Infection

Abstract

During productive infection, herpes simplex virus type 1 (HSV-1) induces the formation of discrete nuclear foci containing cellular chaperone proteins, proteasomal components, and ubiquitinated proteins. These structures are known as VICE domains and are hypothesized to play an important role in protein turnover and nuclear remodeling in HSV-1-infected cells. Here we show that VICE domain formation in Vero and other cells requires the HSV-1 immediate-early protein ICP22. Since ICP22 null mutants replicate efficiently in Vero cells despite being unable to induce VICE domain formation, it can be concluded that VICE domain formation is not essential for HSV-1 productive infection. However, our findings do not exclude the possibility that VICE domain formation is required for viral replication in cells that are nonpermissive for ICP22 mutants. Our studies also show that ICP22 itself localizes to VICE domains, suggesting that it could play a role in forming these structures. Consistent with this, we found that ICP22 expression in transfected cells is sufficient to reorganize the VICE domain component Hsc70 into nuclear inclusion bodies that resemble VICE domains. An N-terminal segment of ICP22, corresponding to residues 1 to 146, is critical for VICE domain formation in infected cells and Hsc70 reorganization in transfected cells. We previously found that this portion of the protein is dispensable for ICP22's effects on RNA polymerase II phosphorylation. Thus, ICP22 mediates two distinct regulatory activities that both modify important components of the host cell nucleus.Soon after herpes simplex virus type 1 (HSV-1) infects a susceptible cell, its genome enters the nucleus. There, the ϳ80 viral genes are transcribed by the host cell RNA polymerase II (Pol II). Viral gene expression occurs in a tightly regulated cascade in which there are three phases of gene expression: the immediate-early (IE), delayed-early (DE), and late (L) phases (reviewed in reference 50). Four of the five IE genes encode proteins that are important regulators of viral gene expression: ICP0, ICP4, ICP22, and ICP27. Production of these proteins is critical for expression of both DE and L genes. Many of the DE genes encode proteins directly or indirectly involved in viral DNA synthesis, and soon after their expression, viral DNA replication commences. The process of DNA replication drives high-level expression of L genes, most of which encode viral structural proteins. Late in infection, capsid assembly and genome packaging occur in the nucleus, and genome-containing capsids are transported to the cytoplasm for maturation and secretion.HSV-1 replication in the nucleus is accompanied by a dramatic physical reorganization of this host cell organelle. Incoming viral genomes interact with ICP4 and ICP27 (13) and nucleate the formation of nuclear domain 10 (ND10/PML)-like bodies (12), which are subsequently disrupted by ICP0 (11). The viral genomes then associate with several other viral and cellular proteins, and these complexes ultimately develop i...

Herpes Simplex Virus 1 ICP22 but Not US1.5 Is Required for Efficient Acute Replication in Mice and VICE Domain Formation

“…7A and B). Notably, our results provide a finer map of the region of ICP22 required for VICE domain formation, reducing it from the first 146 N-terminal residues as previously described (13) to the first 89 N-terminal amino acids. Because the functional significance of VICE domains in the HSV-1 life cycle is not yet fully understood, it is possible that the requirement of VICE domains in viral growth could be cell type dependent and specifically required for in vivo replication.…”

“…Although the significance of this function in viral replication is not clear, it has been proposed that the altered modification of RNA polymerase II either enhances HSV-1 genome transcription or helps suppress cellular transcription (12). Recently, ICP22 was also shown to be required for the formation of virus-induced chaperone-enriched (VICE) domains (13). These domains were initially described to form in response to viral infection (14,15) and contain many chaperone and polyubiquitinated proteins.…”

Identification of Viral and Host Proteins That Interact with Murine Gammaherpesvirus 68 Latency-Associated Nuclear Antigen during Lytic Replication: a Role for Hsc70 in Viral Replication

“…An analogous case may exist for the HSV-1 protein ICP22, which is necessary both for efficient lytic replication in Vero and human embryonic lung (HEL) cells and for VICE domain formation (87,88). HSV-1 mutant TF1.5 expresses N-terminally truncated ICP22 that is unable to promote VICE domain formation while not affecting RNA polymerase II (pol II) modification.…”

Baculovirus IE2 stimulates the expression of heat shock proteins in insect and mammalian cells to facilitate its proper functioning

“…In herpes simplex virus 1, HSP90 is required for the proper nuclear localization of its viral DNA polymerase. HSC70/ HSP70 has also been reported to form a virus-induced chaperone-enriched (VICE) domain that is induced by ICP22 [57] to remove stalled RNA Pol II and aberrant nuclear proteins for productive virus replication within the replication compartment [58][59][60].…”