ORF45 of Kaposi's sarcoma-associated herpesvirus inhibits phosphorylation of interferon regulatory factor 7 by IKKε and TBK1 as an alternative substrate.
Open reading frame 45 (ORF45) of Kaposi's sarcoma-associated herpesvirus (KSHV) is an immediate-early and tegument protein that plays critical roles in antagonizing host antiviral responses. We have previously shown (Zhu et al, Proc. Natl. Acad. Sci. U. S. A., 99:5573-5578, 2002) that ORF45 suppresses activation of interferon regulatory factor 7 (IRF7), a crucial regulator of type I interferon gene expression, by blocking its virus-induced phosphorylation and nuclear accumulation. We report here further characterization of the mechanisms by which ORF45 inhibits IRF7 phosphorylation. In most cell types, IRF7 is phosphorylated and activated by IKKε and TBK1 after viral infection. We found that phosphorylation of IRF7 on Ser477 and Ser479 by IKKε or TBK1 is inhibited by ORF45. The inhibition is specific to IRF7 because phosphorylation of its close relative IRF3 is not affected by ORF45, implying that ORF45 does not inactivate the kinases directly. In fact, we found that ORF45 is phosphorylated efficiently on Ser41 and Ser162 by IKKε and TBK1. We demonstrated that ORF45 competes with the associated IRF7 and inhibits its phosphorylation by IKKε or TBK1 by acting as an alternative substrate.
Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
Qiming
Q
Liang
Bishi
B
Fu
Fayi
F
Wu
Xiaojuan
X
Li
Yan
Y
Yuan
Fanxiu
F
Zhu
D000595:Amino Acid Sequence; D001483:Base Sequence; D001667:Binding, Competitive; D004279:DNA, Viral / Q000235:genetics; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000378:metabolism*; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism*; D050839:Interferon Regulatory Factor-7 / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D013379:Substrate Specificity
D004279:DNA, Viral; C494234:IRF7 protein, human; D017874:Immediate-Early Proteins; D050839:Interferon Regulatory Factor-7; C456286:ORF45 protein, Kaposi's sarcoma-associated herpesvirus; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D012694:Serine; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase