Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.7/444
Título: Human Cytomegalovirus Gene UL76 Induces IL-8 Expression through Activation of the DNA Damage Response
Autor: Costa, Helena
Nascimento, Rute
Sinclair, John
Parkhouse, Robert Michael Evans
Palavras-chave: Humans
Genes, Reporter
DNA Damage
Data: 12-Set-2013
Editora: PLOS
Citação: Costa H, Nascimento R, Sinclair J, Parkhouse RME (2013) Human Cytomegalovirus Gene UL76 Induces IL-8 Expression through Activation of the DNA Damage Response. PLoS Pathog 9(9): e1003609. doi:10.1371/journal.ppat.1003609
Resumo: Human cytomegalovirus (HCMV), a β-herpesvirus, has evolved many strategies to subvert both innate and adaptive host immunity in order to ensure its survival and propagation within the host. Induction of IL-8 is particularly important during HCMV infection as neutrophils, primarily attracted by IL-8, play a key role in virus dissemination. Moreover, IL-8 has a positive effect in the replication of HCMV. This work has identified an HCMV gene (UL76), with the relevant property of inducing IL-8 expression at both transcriptional and protein levels. Up-regulation of IL-8 by UL76 results from activation of the NF-kB pathway as inhibition of both IKK-β activity or degradation of Ikβα abolishes the IL-8 induction and, concomitantly, expression of UL76 is associated with the translocation of p65 to the nucleus where it binds to the IL-8 promoter. Furthermore, the UL76-mediated induction of IL-8 requires ATM and is correlated with the phosphorylation of NEMO on serine 85, indicating that UL76 activates NF-kB pathway by the DNA Damage response, similar to the impact of genotoxic drugs. More importantly, a UL76 deletion mutant virus was significantly less efficient in stimulating IL-8 production than the wild type virus. In addition, there was a significant reduction of IL-8 secretion when ATM -/- cells were infected with wild type HCMV, thus, indicating that ATM is also involved in the induction of IL-8 by HCMV. In conclusion, we demonstrate that expression of UL76 gene induces IL-8 expression as a result of the DNA damage response and that both UL76 and ATM have a role in the mechanism of IL-8 induction during HCMV infection. Hence, this work characterizes a new role of the activation of DNA Damage response in the context of host-pathogen interactions.
Peer review: yes
URI: http://hdl.handle.net/10400.7/444
DOI: 10.1371/journal.ppat.1003609
Versão do Editor: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003609
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