Identification of caspase-mediated decay of interferon regulatory factor-3, exploited by a Kaposi sarcoma-associated herpesvirus immunoregulatory protein.
Upon virus infection, the cell mounts an innate type I interferon (IFN) response to limit the spread. This response is orchestrated by the constitutively expressed IFN regulatory factor (IRF)-3 protein, which becomes post-translationally activated. Although the activation events are understood in detail, the negative regulation of this innate response is less well understood. Many viruses, including Kaposi sarcoma-associated herpesvirus (KSHV), have evolved defense strategies against this IFN response. Thus, KSHV encodes a viral IRF (vIRF)-2 protein, sharing homology with cellular IRFs and is a known inhibitor of the innate IFN response. Here, we show that vIRF-2 mediates IRF-3 inactivation by a mechanism involving caspase-3, although vIRF-2 itself is not pro-apoptotic. Importantly, we also show that caspase-3 participates in normal IRF-3 turnover in the absence of vIRF-2, during the antiviral response induced by poly(I:C) transfection. These data provide unprecedented insight into negative regulation of IRF-3 following activation of the type I IFN antiviral response and the mechanism by which KSHV vIRF-2 inhibits this innate response.
Aresté
Cristina
C
Cancer Research UK Cancer Centre, School of Cancer Sciences, Vincent Drive, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
Mutocheluh
Mohamed
M
Blackbourn
David J
DJ
D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006566:Herpesviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D050835:Interferon Regulatory Factors; D014764:Viral Proteins; C413486:viral interferon regulatory factors; D053148:Caspase 3