A novel mechanism of nuclear factor-kappaB regulation by adenoviral protein 14.7K.
Viruses have evolved many different ways to evade immune attacks. The adenoviral E3 protein 14.7K effectively inhibits antiviral immunity and inflammation. However, the underlying mechanism for this effect is unclear. Here we show that 14.7K is a potent inhibitor of nuclear factor (NF)-kappaB transcriptional activity following Toll-like receptor (TLR) or tumour necrosis factor (TNF) receptor signalling. The inhibition of the NF-kappaB activity occurs downstream of IkappaBalpha degradation and NF-kappaB translocation into the nucleus. Analysis of NF-kappaB DNA binding reveals that 14.7K specifically inhibits p50 homodimer DNA binding and that this inhibition is mediated through the interaction of 14.7K with p50. We propose that 14.7K inhibits NF-kappaB activity through directly blocking p50 binding to DNA and that this is the basis for its anti-inflammatory properties. Our data also indicate a role for p50 homodimer-dependent transcription in inflammation.
Carmody
Ruaidhrí J
RJ
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.
Maguschak
Kimberly
K
Chen
Youhai H
YH
D017503:Adenovirus E3 Proteins / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011401:Promoter Regions, Genetic; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects
D017503:Adenovirus E3 Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; C509184:E3 14.7K protein, Adenovirus; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606205:Nfkbia protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D051193:Toll-Like Receptors; D000072000:NF-KappaB Inhibitor alpha