ASC-mediated NF-κB Activation Leading to Interleukin-8 Production Requires Caspase-8 and Is Inhibited by CLARP

• Published in: The Journal of biological chemistry 2005-04, Vol.280 (15), p.15122-15130
• Main Authors: Hasegawa, Mizuho, Imamura, Ryu, Kinoshita, Takeshi, Matsumoto, Norihiko, Masumoto, Junya, Inohara, Naohiro, Suda, Takashi
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M412284200

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-κB 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-κB 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-κB activation, and that the ASC-mediated NF-κB activation actually induces physiologically relevant gene expression.