期刊
PLOS PATHOGENS
卷 5, 期 10, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1000635
关键词
-
资金
- University of Florida College of Medicine
- NIH [U54 AI057157]
NF-kappa B and inflammasomes both play central roles in orchestrating anti-pathogen responses by rapidly inducing a variety of early-response cytokines and chemokines following infection. Myxoma virus (MYXV), a pathogenic poxvirus of rabbits, encodes a member of the cellular pyrin domain (PYD) superfamily, called M013. The viral M013 protein was previously shown to bind host ASC-1 protein and inhibit the cellular inflammasome complex that regulates the activation and secretion of caspase 1-regulated cytokines such as IL-1 beta and IL-18. Here, we report that human THP-1 monocytic cells infected with a MYXV construct deleted for the M013L gene (vMyxM013-KO), in stark contrast to the parental MYXV, rapidly induce high levels of secreted pro-inflammatory cytokines like TNF, IL-6, and MCP-1, all of which are regulated by NF-kappa B. The induction of these NF-kappa B regulated cytokines following infection with vMyxM013-KO was also confirmed in vivo using THP-1 derived xenografts in NOD-SCID mice. vMyxM013-KO virus infection specifically induced the rapid phosphorylation of IKK and degradation of I kappa B alpha, which was followed by nuclear translocation of NF-kappa B/p65. Even in the absence of virus infection, transiently expressed M013 protein alone inhibited cellular NF-kappa B-mediated reporter gene expression and nuclear translocation of NF-kappa B/p65. Using protein/protein interaction analysis, we show that M013 protein also binds directly with cellular NF-kappa B1, suggesting a direct physical and functional linkage between NF-kappa B1 and ASC-1. We further demonstrate that inhibition of the inflammasome with a caspase-1 inhibitor did not prevent the induction of NF-kappa B regulated cytokines following infection with vMyxM013-KO virus, but did block the activation of IL-1 beta. Thus, the poxviral M013 inhibitor exerts a dual immuno-subversive role in the simultaneous co-regulation of both the cellular inflammasome complex and NF-kappa B-mediated pro-inflammatory responses.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据