title: Cellular localization of the herpes simplex virus ICP0 protein dictates its ability to block IRF3-mediated innate immune responses.
abstract: Interferon regulatory factor 3 (IRF3) is important for innate antiviral responses; accordingly, many viruses target and inactivate IRF3. The ability of the Herpes simplex virus type 1 (HSV-1) immediate early protein ICP0 to inhibit IRF3 is controversial and has not been studied solely in the context of a wild type HSV-1 infection. Discrepancies in the literature surround the mechanism by which ICP0 antagonizes the IRF3 pathway, the cellular localization of ICP0 inhibitory activity and the ability of ICP0 to interfere with interferon and interferon-stimulated gene induction. In this study, we set out to investigate the role of ICP0 localization and the requirement of the proteasome during the inhibition of IRF3 activation within the context of an HSV-1 infection. Collectively, the results presented herein demonstrate that incoming wild type HSV-1 activates IRF3 and that de novo produced ICP0 prevents sustained IRF3 activation following its translocation from the nucleus to the cytoplasm. While previous studies implicate the E3 ubiquitin ligase domain of ICP0 in mediating its biological functions, including the inhibition of IRF3, we show that cytoplasmic ICP0 does not require the proteasome for this activity. Instead, proteasome function is required to localize ICP0 to the cytoplasm where it mediates its inhibitory effect independent of E3 ubiquitin ligase activity. The importance of these findings is discussed within the context of an HSV-1 infection.
authors.affiliation: Department of Pathology and Molecular Medicine, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Paladino
authors.forename: Susan E
authors.initials: SE
authors.lastname: Collins
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mossman
mesh_terms: D021581:Active Transport, Cell Nucleus; D002478:Cells, Cultured; D003593:Cytoplasm; D006561:Herpes Simplex; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000032:analysis / Q000276:immunology; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D014764:Viral Proteins / Q000032:analysis / Q000276:immunology*
chemical_list: C494232:IRF3 protein, human; D017874:Immediate-Early Proteins; D050838:Interferon Regulatory Factor-3; D014764:Viral Proteins; D046988:Proteasome Endopeptidase Complex
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