Recruitment of activated IRF-3 and CBP/p300 to herpes simplex virus ICP0 nuclear foci: Potential role in blocking IFN-β induction

Abstract

The host innate response to viral infection includes the production of interferons, which is dependent on the coordinated activity of multiple transcription factors. Herpes simplex virus 1 (HSV-1) has been shown to block efficient interferon expression by multiple mechanisms. We and others have demonstrated that HSV-1 can inhibit the transcription of genes promoted by interferon regulatory factor-3 (IRF-3), including interferon beta (IFN-beta), and that the immediate-early ICP0 protein is sufficient for this function. However, the exact mechanism by which ICP0 blocks IRF-3 activity has yet to be determined. Unlike some other viral proteins that inhibit IRF-3 activity, ICP0 does not appear to affect phosphorylation and dimerization of IRF-3. Here, we show that a portion of activated IRF-3 co-localizes with nuclear foci containing ICP0 at early times after virus infection. Co-localization to ICP0-containing foci is also seen with the IRF-3-binding partners and transcriptional co-activators, CBP and p300. In addition, using immunoprecipitation of infected cell lysates, we can immunoprecipitate a complex containing ICP0, IRF-3, and CBP. Thus we hypothesize that ICP0 recruits activated IRF-3 and CBP/p300 to nuclear structures, away from the host chromatin. This leads to the inactivation and accelerated degradation of IRF-3, resulting in reduced transcription of IFN-beta and an inhibition of the host response. Therefore, ICP0 provides an example of how viruses can block IFN-beta induction by sequestration of important transcription factors essential for the host response.

Control of TANK-binding Kinase 1-mediated Signaling by the γ134.5 Protein of Herpes Simplex Virus 1

“…Moreover, an immediate early protein ICP0 confers viral resistance to IFN by disseminating promyelocytic leukemia protein (52,53). Notably, ICP0 also inhibits the induction of IFNresponsive genes, where it sequesters or promotes partial IRF3 degradation (21)(22)(23). Recent studies show that another immediate early protein ICP27 is required to suppress cytokine induction mediated by IRF3 in macrophage dendritic cells and embryonic fibroblasts (1,25).…”

“…Furthermore, an HSV mutant, with deletion in immediate early protein ICP0, induces ISG56 expression (21). Accordingly, expression of ICP0 inhibits the induction of antiviral programs mediated by IRF3 or IRF7 (21)(22)(23). However, although ICP0 negatively regulates IFN-␤ expression, it is not essential for this effect (24).…”

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

“…Rotavirus non-structural protein 1 (NSP1) also targets IRF-3 for degradation (Graff et al, 2007), as well as IRF-5 and IRF-7 (Barro & Patton, 2007). Similarly, ICP0 of HSV-1 inhibits IRF-3 and IRF-7 (Lin et al, 2004a;Melroe et al, 2004), reportedly by recruiting activated IRF-3 and CBP/p300 to nuclear structures away from host chromatin (Melroe et al, 2007). In contrast, it appears that bovine herpesvirus 1 (BHV-1) bICP0 targets IRF-3 for degradation (Saira et al, 2007).…”

Human Bocavirus NP1 Inhibits IFN-β Production by Blocking Association of IFN Regulatory Factor 3 with IFNB Promoter

“…36,37). Only a limited number of viral proteins was reported to interfere with the function of activated IRF-3 in the nucleus (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51).…”