Cytomegalovirus activates interferon immediate-early response gene expression and an interferon regulatory factor 3-containing interferon-stimulated response element-binding complex.
Interferon establishes an antiviral state in numerous cell types through the induction of a set of immediate-early response genes. Activation of these genes is mediated by phosphorylation of latent transcription factors of the STAT family. We found that infection of primary foreskin fibroblasts with human cytomegalovirus (HCMV) causes selective transcriptional activation of the alpha/beta-interferon-responsive ISG54 gene. However, no activation or nuclear translocation of STAT proteins was detected. Activation of ISG54 occurs independent of protein synthesis but is prevented by protein tyrosine kinase inhibitors. Further analysis revealed that HCMV infection induced the DNA binding of a novel complex, tentatively called cytomegalovirus-induced interferon-stimulated response element binding factor (CIF). CIF is composed, at least in part, of the recently identified interferon regulatory factor 3 (IRF3), but it does not contain the STAT1 and STAT2 proteins that participate in the formation of interferon-stimulated gene factor 3. IRF3, which has previously been shown to possess no intrinsic transcriptional activation potential, interacts with the transcriptional coactivator CREB binding protein, but not with p300, to form CIF. Activating interferon-stimulated genes without the need for prior synthesis of interferons might provide the host cell with a potential shortcut in the activation of its antiviral defense.
Navarro
L
L
Department of Biology, University of California at San Diego, La Jolla, California 92093, USA.
Mowen
K
K
Rodems
S
S
Weaver
B
B
Reich
N
N
Spector
D
D
David
M
M
D015075:2-Aminopurine / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D003587:Cytomegalovirus / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016601:RNA-Binding Proteins; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D019311:Staurosporine / Q000494:pharmacology; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C484289:IFIT2 protein, human; C494257:IRF1 protein, human; C494229:IRF2 protein, human; C494232:IRF3 protein, human; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D010750:Phosphoproteins; D011500:Protein Synthesis Inhibitors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D015075:2-Aminopurine; D016899:Interferon-beta; D003513:Cycloheximide; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D019892:eIF-2 Kinase; D011493:Protein Kinase C; D019311:Staurosporine