Major Human Cytomegalovirus Structural Protein pp65 (ppUL83) Prevents Interferon Response Factor 3 Activation in the Interferon Response

Abstract

We have identified a cytomegalovirus virion protein capable of modulating the rapid induction of an interferon-like response in cells that follows virus binding and penetration. Functional genomics revealed a role for the major cytomegalovirus structural protein, pp65 (ppUL83), in counteracting this response. The underlying mechanism involves a differential impact of this structural protein on the regulation of interferon response factor 3 (IRF-3). In contrast, NF-B is activated independent of pp65, and neither STAT1 nor STAT3 becomes activated by either virus. pp65 is sufficient to prevent the activation of IRF-3 when introduced alone into cells. pp65 acts by inhibiting nuclear accumulation of IRF-3 and is associated with a reduced IRF-3 phosphorylation state. Thus, this investigation shows that the major structural protein of cytomegalovirus is committed to the modulation of the IRF-3 response, a primary mediator of the type I interferon response. By subverting IRF-3, the virus escapes throwing a central alarm devoted to both immediate antiviral control and regulation of the immune response.

Human Cytomegalovirus Alters Localization of MHC Class II and Dendrite Morphology in Mature Langerhans Cells

“…In addition, Odeberg et al (49) found that transfection of pp65 led to reduced surface and increased perinuclear localization of MHC class II molecules in IFN-␥-treated fibroblasts. pp65 has recently been shown to inhibit components of the type I IFN response in fibroblasts and PBMC (50), but a mechanistic link to MHC class II localization remains to be identified. Work on other pathogens has revealed several nonhomologous microbial proteins, with presumably distinct host targets, that each induce intracellular accumulation of mature, peptide-loaded MHC class II molecules (51,52).…”

Mouse cytomegalovirus inhibits beta interferon (IFN-β) gene expression and controls activation pathways of the IFN-β enhanceosome

“…4) and downregulates the basal NF-kB activity. The HCMV tegument protein pp65 (pUL83) was reported to counteract innate antiviral defence, including NF-kB activity (Browne & Shenk, 2003) and IRF3 activation (Abate et al, 2004). In addition, an indirect effect on inhibition of IFN-b expression by deletion of the UL83-ORF was described previously (Taylor & Bresnahan, 2006b) DCs respond to MCMV with a strong type I IFN production (Krug et al, 2004;Tabeta et al, 2004;Delale et al, 2005;Andoniou et al, 2005).…”

“…protein kinase R and RNaseL (Child et al, 2004(Child et al, , 2006Valchanova et al, 2006). A HCMV mutant lacking UL83 was found to be deficient in inhibition of IFNb gene expression, leading to the conclusions that pUL83/ pp65 interferes with IRF3-or NF-kB-mediated gene induction (Browne & Shenk, 2003;Abate et al, 2004). Moreover, the HCMV IE2 protein pp86 was identified as blocking IFN-b gene induction by inhibiting NF-kB DNA binding (Taylor & Bresnahan, 2006a).…”

Functional Characterization of Kaposi's Sarcoma-Associated Herpesvirus ORF45 byBacterial Artificial Chromosome-Based Mutagenesis

“…The HSV-1 virion host shutoff protein (UL41) is known to degrade host mRNA and shut down the host translation program (32). Cytomegalovirus abundant tegument protein pp65 is able to suppress a subset of interferon-stimulated genes during infection (1,6). Second, some tegument proteins play roles in transport of capsids to the nucleus after the virus enters a host cell.…”