Herpes simplex virus disrupts NF-kappaB regulation by blocking its recruitment on the IkappaBalpha promoter and directing the factor on viral genes |
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Authors: | Amici Carla Rossi Antonio Costanzo Antonio Ciafrè Stefania Marinari Barbara Balsamo Mirna Levrero Massimo Santoro M Gabriella |
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Institution: | Department of Biology and Dermatology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy. |
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Abstract: | 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. |
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