ASC-mediated NF-κB activation leading to interleukin-8 production requires caspase-8 and is inhibited by CLARP
ASC-mediated NF-κB activation leading to interleukin-8 production requires caspase-8 and is inhibited by CLARP
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DOI：
10.1074/jbc.m412284200
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发表时间：
2005-04-15
影响因子：
4.8
通讯作者：
Suda, T
中科院分区：
文献类型：
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作者：
Hasegawa, M;Imamura, R;Suda, T
ASC是一种接头分子，介导几种APAF-1类分子的凋亡和炎症信号，包括CARD12/IPAF、低温比林/PYPAF1、PYPAF5、PYPAF7和NALP1。为了研究ASC介导的信号通路，我们建立了细胞系，在该细胞系中，另一个类似APAF-1的分子NOD2识别的细菌成分胞壁二肽诱导CARD12-NOD2嵌合蛋白与ASC相互作用，并诱导细胞自主激活NF-kappa B。这一反应需要caspase-8，并被caspase-8的抑制剂CLARP/Flip抑制。当caspase-8在内源性水平表达时，caspase-8的催化活性是ASC介导的NF-kappa B激活所必需的，而当caspase-8过表达时，caspase-8的催化活性并不是必需的。相反，FADD，连接Fas和caspase-8的接头蛋白，不是这种反应所必需的。ASC一贯地将caspase-8和CLARP招募到其细胞内的斑点状聚集体中，而不是FADD和NOD2。最后，胞浆二肽可诱导MAIL8细胞产生IL-8。这些结果首次表明caspase-8在Asc介导的NF-kappa B激活中起重要作用，并且Asc介导的NF-kappa B激活实际上诱导了生理相关基因的表达。
ASC is an adaptor molecule that mediates apoptotic and inflammatory signals from several Apaf-1-like molecules, including CARD12/Ipaf, cryopyrin/PYPAF1, PYPAF5, PYPAF7, and NALP1. To characterize the signaling pathway mediated by ASC, we established cell lines in which muramyl dipeptide, the bacterial component recognized by another Apaf-1-like molecule, Nod2, induced an interaction between a CARD12-Nod2 chimeric protein and ASC, and elicited cell autonomous NF-kappa B activation. This response required caspase-8, and was suppressed by CLARP/FLIP, an inhibitor of caspase-8. The catalytic activity of caspase-8 was required for the ASC-mediated NF-kappa B activation when caspase-8 was expressed at an endogenous level, although it was not essential when caspase-8 was overexpressed. In contrast, FADD, the adaptor protein linking Fas and caspase-8, was not required for this response. Consistently, ASC recruited caspase-8 and CLARP but not FADD and Nod2 to its speck-like aggregates in cells. Finally, muramyl dipeptide induced interleukin-8 production in MAIL8 cells. These results are the first to indicate that caspase-8 plays an important role in the ASC-mediated NF-kappa B activation, and that the ASC-mediated NF-kappa B activation actually induces physiologically relevant gene expression.