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Molecular and Cellular Biology, April 2004, p. 2627-2636, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.2627-2636.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

N-Terminal Fragment of c-FLIP(L) Processed by Caspase 8 Specifically Interacts with TRAF2 and Induces Activation of the NF-{kappa}B Signaling Pathway

Takao Kataoka1* and Jürg Tschopp2

Division of Bioinformatics, Center for Biological Resources and Informatics, Tokyo Institute of Technology, Midori-ku, Yokohama 226-8501, Japan,1 Institute of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland2

Received 22 October 2003/ Returned for modification 21 November 2003/ Accepted 5 January 2004

Caspase 8 is required not only for death receptor-mediated apoptosis but also for lymphocyte activation in the immune system. FLIP(L), the long-splice form of c-FLIP, is one of the specific substrates for caspase 8, and increased expression of FLIP(L) promotes activation of the NF-{kappa}B signaling pathway. The synthetic caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) markedly blocked NF-{kappa}B activation induced by overexpression of FLIP(L). FLIP(L) is specifically processed by caspase 8 into N-terminal FLIP(p43) and C-terminal FLIP(p12). Only FLIP(p43) was able to induce NF-{kappa}B activation as efficiently as FLIP(L), and FLIP(p43)-induced NF-{kappa}B activation became insensitive to zVAD-fmk. In caspase 8-deficient cells, FLIP(p43) provoked NF-{kappa}B activation only when procaspase 8 or caspase 8(p43) was complemented. FLIP(p43)-induced NF-{kappa}B activation was profoundly blocked by the dominant-negative TRAF2. Moreover, endogenous TRAF2 interacted specifically with FLIP(p43), and the formation of the FLIP(p43)-caspase 8-TRAF2 tertiary complex was a prerequisite to induction of NF-{kappa}B activation. zVAD-fmk prevented the recruitment of TRAF2 into the death-inducing signaling complex. Thus, our present results demonstrate that FLIP(p43) processed by caspase 8 specifically interacts with TRAF2 and subsequently induces activation of the NF-{kappa}B signaling pathway.

* Corresponding author. Mailing address: Division of Bioinformatics, Center for Biological Resources and Informatics, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan. Phone: 81-45-924-5830. Fax: 81-45-924-5832. E-mail: tkataoka{at}bio.titech.ac.jp.

Molecular and Cellular Biology, April 2004, p. 2627-2636, Vol. 24, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.7.2627-2636.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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