Human cytomegalovirus IE86 attenuates virus- and tumor necrosis factor alpha-induced NFkappaB-dependent gene expression.
Human cytomegalovirus (HCMV) infection regulates a number of genes involved in the host antiviral response. We have previously reported that HCMV attenuates the expression of beta interferon (IFN-beta) and a number of proinflammatory chemokines, and this attenuation is mediated by the HCMV immediate-early protein IE86. The present study seeks to identify the mechanism by which IE86 blocks IFN-beta expression. We demonstrate that the induction of IFN-beta during HCMV infection requires the activation of both the IRF-3 and the NFkappaB pathways. Therefore, IE86 may target either pathway to block IFN-beta expression. Our results show that IE86 does not block IRF-3 phosphorylation, dimerization, nuclear translocation, or target gene expression. However, using gel shift analysis, we demonstrate that IE86 efficiently inhibits virus-induced binding of NFkappaB to the IFN-beta promoter, resulting in attenuation of IFN-beta and NFkappaB-dependent gene expression. Furthermore, IE86 expression inhibits tumor necrosis factor alpha-induced NFkappaB DNA binding and target gene expression. Together, these results identify IE86 as a NFkappaB antagonist, which results in the suppression of NFkappaB-dependent cytokine and chemokine gene expression.
Taylor
R Travis
RT
University of Minnesota, Department of Microbiology, 1060 Mayo Building, MMC196, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Bresnahan
Wade A
WA
D001483:Base Sequence; D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000821:virology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000235:genetics; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004279:DNA, Viral; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D004247:DNA