Shapira Sagi, Harb Omar S, Margarit Juan, Matrajt Mariana, Han Jerry, Hoffmann Alexander, Freedman Bruce, May Michael J, Roos David S, Hunter Christopher A
Department of Pathobiology, University of Pennsylvania, Philadelphia PA 19104, USA.
J Cell Sci. 2005 Aug 1;118(Pt 15):3501-8. doi: 10.1242/jcs.02428.
Signaling via the NF-kappaB cascade is critical for innate recognition of microbial products and immunity to infection. As a consequence, this pathway represents a strong selective pressure on infectious agents and many parasitic, bacterial and viral pathogens have evolved ways to subvert NF-kappaB signaling to promote their survival. Although the mechanisms utilized by microorganisms to modulate NF-kappaB signaling are diverse, a common theme is targeting of the steps that lead to IkappaB degradation, a major regulatory checkpoint of this pathway. The data presented here demonstrate that infection of mammalian cells with Toxoplasma gondii results in the activation of IKK and degradation of IkappaB. However, despite initiation of these hallmarks of NF-kappaB signaling, neither nuclear accumulation of NF-kappaB nor NF-kappaB-driven gene expression is observed in infected cells. However, this defect was not due to a parasite-mediated block in nuclear import, as general nuclear import and constitutive nuclear-cytoplasmic shuttling of NF-kappaB remain intact in infected cells. Rather, in T. gondii-infected cells, the termination of NF-kappaB signaling is associated with reduced phosphorylation of p65/RelA, an event involved in the ability of NF-kappaB to translocate to the nucleus and bind DNA. Thus, these studies demonstrate for the first time that the phosphorylation of p65/RelA represents an event downstream of IkappaB degradation that may be targeted by pathogens to subvert NF-kappaB signaling.
通过核因子-κB（NF-κB）级联反应进行的信号传导对于微生物产物的天然识别和抗感染免疫至关重要。因此，该信号通路对感染因子构成了强大的选择压力，许多寄生虫、细菌和病毒病原体都进化出了破坏NF-κB信号传导以促进自身存活的方式。尽管微生物用于调节NF-κB信号传导的机制多种多样，但一个共同的主题是针对导致IκB降解的步骤，这是该信号通路的一个主要调节关卡。本文提供的数据表明，用刚地弓形虫感染哺乳动物细胞会导致IKK激活和IκB降解。然而，尽管启动了NF-κB信号传导的这些标志性事件，但在感染细胞中既未观察到NF-κB的核内积累，也未观察到NF-κB驱动的基因表达。然而，这种缺陷并非由于寄生虫介导的核输入受阻，因为在感染细胞中，NF-κB的一般核输入和组成型核质穿梭仍然完好无损。相反，在刚地弓形虫感染的细胞中，NF-κB信号传导的终止与p65/RelA磷酸化减少有关，这一事件涉及NF-κB转运至细胞核并结合DNA的能力。因此，这些研究首次证明，p65/RelA的磷酸化代表了IκB降解下游的一个事件，病原体可能针对该事件来破坏NF-κB信号传导。
