Human Cytomegalovirus Gene UL76 Induces IL-8 Expression through Activation of the DNA Damage Response

PLoS Pathogens

John Sinclair¹  Helena Costa²  Robert Michael Evans Parkhouse²  Rute Nascimento² 

[1] Department of Medicine, University of Cambridge, Cambridge, United Kingdom;Instituto Gulbenkian de Ciência, Oeiras, Portugal

关键词: 293T cells;    DNA damage;    Luciferase;    Enzyme-linked immunoassays;    Human cytomegalovirus;    Immunoprecipitation;    Viral replication;    Phosphorylation;   

DOI  :  10.1371/journal.ppat.1003609

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY