Herpes simplex virus disrupts NF-kappaB regulation by blocking its recruitment on the IkappaBalpha promoter and directing the factor on viral genes.
Herpes simplex viruses (HSVs) are able to hijack the host-cell IkappaB kinase (IKK)/NF-kappaB pathway, which regulates critical cell functions from apoptosis to inflammatory responses; however, the molecular mechanisms involved and the outcome of the signaling dysregulation on the host-virus interaction are mostly unknown. Here we show that in human keratinocytes HSV-1 attains a sophisticated control of the IKK/NF-kappaB pathway, inducing two distinct temporally controlled waves of IKK activity and disrupting the NF-kappaB autoregulatory mechanism. Using chromatin immunoprecipitation we demonstrate that dysregulation of the NF-kappaB-response is mediated by a virus-induced block of NF-kappaB recruitment to the promoter of the IkappaBalpha gene, encoding the main NF-kappaB-inhibitor. We also show that HSV-1 redirects NF-kappaB recruitment to the promoter of ICP0, an immediate-early viral gene with a key role in promoting virus replication. The results reveal a new level of control of cellular functions by invading viruses and suggest that persistent NF-kappaB activation in HSV-1-infected cells, rather than being a host response to the virus, may play a positive role in promoting efficient viral replication.
Amici
Carla
C
Department of Biology and Dermatology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy.
Rossi
Antonio
A
Costanzo
Antonio
A
Ciafrè
Stefania
S
Marinari
Barbara
B
Balsamo
Mirna
M
Levrero
Massimo
M
Santoro
M Gabriella
MG
D015153:Blotting, Western; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000737:chemistry; D005786:Gene Expression Regulation; D005814:Genes, Viral; D018259:Herpesvirus 1, Human / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D017874:Immediate-Early Proteins / Q000378:metabolism; D007249:Inflammation; D015603:Keratinocytes / Q000378:metabolism; D008957:Models, Genetic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011454:Prostaglandins A / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D018139:Simplexvirus / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014466:Ultraviolet Rays
D017931:DNA Primers; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011454:Prostaglandins A; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; C100573:prostaglandin A1