title: Recruitment of activated IRF-3 and CBP/p300 to herpes simplex virus ICP0 nuclear foci: Potential role in blocking IFN-beta 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.
authors.affiliation: Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Melroe
authors.forename: Lindsey
authors.initials: L
authors.lastname: Silva
authors.forename: Priscilla A
authors.initials: PA
authors.lastname: Schaffer
authors.forename: David M
authors.initials: DM
authors.lastname: Knipe
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000378:metabolism*; D047468:Immunoprecipitation; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D016899:Interferon-beta / Q000096:biosynthesis*; D007976:Leupeptins / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D017874:Immediate-Early Proteins; D050838:Interferon Regulatory Factor-3; D007976:Leupeptins; D016899:Interferon-beta; D050880:p300-CBP Transcription Factors; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde