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J. Biol. Chem., Vol. 280, Issue 8, 6923-6932, February 25, 2005

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A Novel Caspase-2 Complex Containing TRAF2 and RIP1^*

Mohamed Lamkanfi, Kathleen D'hondt, Lieselotte Vande Walle, Marjan van Gurp, Geertrui Denecker, Jill Demeulemeester, Michael Kalai¶, Wim Declercq, Xavier Saelens, and Peter Vandenabeele||

From the Unit of Molecular Signalling and Cell Death, Department for Molecular Biomedical Research, Ghent University and Flemish Interuniversity Institute for Biotechnology, Technologiepark 927, Zwijnaarde B-9052, Belgium

The enzymatic activity of caspases is implicated in the execution of apoptosis and inflammation. Here we demonstrate a novel nonenzymatic function for caspase-2 other than its reported proteolytic role in apoptosis. Caspase-2, unlike caspase-3, -6, -7, -9, -11, -12, and -14, is a potent inducer of NF-B and p38 MAPK activation in a TRAF2-mediated way. Caspase-2 interacts with TRAF1, TRAF2, and RIP1. Furthermore, we demonstrate that endogenous caspase-2 is recruited into a large and inducible protein complex, together with TRAF2 and RIP1. Structure-function analysis shows that NF-B activation occurs independent of enzymatic activity of the protease and that the caspase recruitment domain of caspase-2 is sufficient for the activation of NF-B and p38 MAPK. These results demonstrate the inducible assembly of a novel protein complex consisting of caspase-2, TRAF2, and RIP1 that activates NF-B and p38 MAPK through the caspase recruitment domain of caspase-2 independently of its proteolytic activity.

Received for publication, September 29, 2004 , and in revised form, November 30, 2004.

^* This work was supported by Interuniversity Attraction Poles Programme-Belgian Science Policy, Fund for Scientific Research-Flanders (FWO-VI) Grants 31.5189.00 and 3G.0006.01, Belgian Federation Against Cancer, Project QLRT-CT-199900739 cofinanced by the European Commission (Research and Technological Development) and Ghent University, and Ghent University Concerted Research Actions (GOA) Project 12050502. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Doctoral fellow with the Institute for Science and Technology (IWT).

A postdoctoral fellow with the Fund for Scientific Research-Flanders (FWO).

^¶ Present address: Institut Pasteur of Brussels, Engelandstraat 642, Brussels B-1180, Belgium.

^|| To whom correspondence should be addressed: Technologiepark 927, Zwijnaarde B-9052, Belgium. Tel.: 32-9-33-13-760; Fax: 32-9-33-13-609; E-mail: peter.vandenabeele{at}dmbr.ugent.be.

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