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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >NF-κB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1
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NF-κB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1

机译：caspase-1调节Toll-IL-1受体域蛋白MyD88接头样蛋白激活NF-κB

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摘要

Toll-like receptors (TLRs)-2 and -4 are important proteins in innate immunity, recognizing microbial products and eliciting host defense responses. Both use the adapter proteins MyD88 and MyD88 adapter-like (Mal) to activate signaling pathways. Here we report that Mal but not MyD88 interacts with caspase-1, the enzyme that processes the precursors of the proinflammatory cytokines IL-1β and IL-18. The interaction was found in a yeast two-hybrid screen and was confirmed by reciprocal GST pull-downs and coimmunoprecipitation of endogenous proteins. We were unable to implicate Mal in regulating caspase-1 activation. However, we found that Mal was cleaved by caspase-1 and that inhibition of caspase-1 activity blocked TLR2- and TLR4-mediated NF-κB and p38 MAP kinase activation but not IL-1 or TLR7 signaling, which are Mal independent. These responses, and the induction of TNF, were also attenuated in caspase-1-deficient cells. Finally, unlike wild-type Mal, a mutant Mal, which was not cleaved by caspase-1, was unable to signal and acted as a dominant negative inhibitor of TLR2 and TLR4 signaling. Our study therefore reveals a role for caspase-1 in the regulation of TLR2 and TLR4 signaling pathways via an effect on Mal. This functional interaction reveals an important aspect of the coordination between TLRs and caspase-1 during the innate response to pathogens.
机译：Toll样受体（TLRs）-2和-4是先天免疫中的重要蛋白质，可识别微生物产物并引发宿主防御反应。两者都使用接头蛋白MyD88和MyD88接头样（Mal）激活信号通路。在这里，我们报道Mal但MyD88没有与caspase-1相互作用，该酶处理促炎性细胞因子IL-1β和IL-18的前体。该相互作用在酵母双杂交筛选中发现，并通过相互的GST下拉和内源蛋白的共免疫沉淀得到证实。我们无法暗示Mal调节caspase-1激活。但是，我们发现Mal可以被caspase-1切割，并且对caspase-1活性的抑制会阻止TLR2和TLR4介导的NF-κB和p38 MAP激酶激活，但不会阻止IL-1或TLR7信号传导，而Mal无关。这些反应和TNF的诱导在caspase-1缺陷细胞中也减弱了。最后，与野生型Mal不同，突变型Mal没有被caspase-1切割，无法发出信号，并充当TLR2和TLR4信号的主要负性抑制剂。因此，我们的研究揭示了caspase-1在通过影响Mal来调节TLR2和TLR4信号通路中的作用。这种功能性相互作用揭示了对病原体的先天应答过程中TLR和caspase-1之间协调的重要方面。

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