Human cytomegalovirus gene UL76 induces IL-8 expression through activation of the DNA damage response.
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.
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Helena
H
Costa
Rute
R
Nascimento
John
J
Sinclair
Robert Michael Evans
RM
Parkhouse
D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000821:virology; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000378:metabolism / Q000821:virology; D004249:DNA Damage; D017930:Genes, Reporter; D054884:Host-Pathogen Interactions; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D021381:Protein Transport; D059748:Proteolysis; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014779:Virus Replication
C508606:CXCL8 protein, human; C491731:IKBKG protein, human; D016209:Interleukin-8; C498143:RELA protein, human; D011994:Recombinant Proteins; D015534:Trans-Activators; D051996:Transcription Factor RelA; C415646:UL76 protein, cytomegalovirus; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051550:I-kappa B Kinase