Molestina Robert E, Sinai Anthony P
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
J Cell Sci. 2005 Dec 15;118(Pt 24):5785-96. doi: 10.1242/jcs.02709.
Activation of NF-kappaB by the intracellular pathogen Toxoplasma gondii is associated with the localization of phosphorylated IkappaB alpha to the parasitophorous vacuole membrane (PVM). This is mediated by a parasite-derived IkappaB kinase (TgIKK) activity and is independent of host IKK function. In the present study, we examined the roles of host IKK and parasite-derived TgIKK on the temporal modulation of NF-kappaB activation. Despite the presence of TgIKK activity at the PVM, nuclear translocation of NF-kappaB and subsequent gene expression exhibited a requirement for the host IKK complex. A detailed kinetic analysis of NF-kappaB activation revealed a biphasic, hierarchical and temporally regulated response. We propose a novel paradigm for the modulation of NF-kappaB-dependent gene expression by T. gondii that involves both the host IKK complex and TgIKK activity at different phases of infection. Thus, T. gondii effectively alters gene expression in a temporal dimension by exploiting the NF-kappaB signaling machinery and subsequently rewiring the activation circuits of the infected host cell.
细胞内病原体弓形虫激活核因子κB（NF-κB）与磷酸化的IκBα定位于寄生泡膜（PVM）有关。这由寄生虫衍生的IκB激酶（TgIKK）活性介导，且独立于宿主IKK功能。在本研究中，我们研究了宿主IKK和寄生虫衍生的TgIKK在NF-κB激活的时间调节中的作用。尽管在PVM处存在TgIKK活性，但NF-κB的核转位及随后的基因表达表现出对宿主IKK复合物的需求。对NF-κB激活的详细动力学分析揭示了一种双相、分级且受时间调节的反应。我们提出了一种由弓形虫调节NF-κB依赖性基因表达的新范式，该范式涉及感染不同阶段的宿主IKK复合物和TgIKK活性。因此，弓形虫通过利用NF-κB信号传导机制并随后重新连接受感染宿主细胞的激活回路，有效地在时间维度上改变基因表达。
