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J. Biol. Chem., Vol. 278, Issue 31, 29216-29230, August 1, 2003

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Caspase-mediated Cleavage Converts the Tumor Necrosis Factor (TNF) Receptor-associated Factor (TRAF)-1 from a Selective Modulator of TNF Receptor Signaling to a General Inhibitor of NF-B Activation^*

Frank Henkler , Bernd Baumann , Mariola Fotin-Mleczek , Monika Weingärtner , Ralph Schwenzer , Nathalie Peters , Angela Graness , Thomas Wirth , Peter Scheurich , Johannes A. Schmid ¶ and Harald Wajant  ||

From the Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany, the Department of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany, and the ^¶Department of Vascular Biology and Thrombosis Research, University of Vienna, 1235 Vienna, Austria

The role of tumor necrosis factor (TNF) receptor-associated factor (TRAF)-1 in NF-B activation by various members of the TNF receptor family is not well understood, and conflicting data have been published. Here, we show that TRAF1 differentially affects TRAF2 recruitment and activation of NF-B by members of the TNF receptor family. Interestingly, a naturally occurring caspase-derived cleavage product of TRAF1 solely comprising its TRAF domain (TRAF1-(164–416)) acted as a general inhibitor of NF-B activation. In contrast, a corresponding fragment generated by cleavage of TRAF3 showed no effect in this regard. In accordance with these functional data, TRAF1, but not TRAF3, interacted with the IKK complex via its N-TRAF domain. Endogenous TRAF1 and the overexpressed TRAF domain of TRAF1 were found to be constitutively associated with the IKK complex, whereas endogenous receptor interacting protein was only transiently associated with the IKK complex upon TNF stimulation. Importantly, the caspase-generated TRAF1-fragment, but not TRAF1 itself inhibited IKK activation. Our results suggest that TRAF1 and TRAF1-(164–416) exert their regulatory effects on receptor-induced NF-B activation not only by modulation of TRAF2 receptor interaction but especially TRAF1-(164–416) also by directly targeting the IKK complex.

Received for publication, October 30, 2002 , and in revised form, March 17, 2003.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants Wa 1025/3-1, SFB 495/A5, and SFB 497/B1. 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.

^|| To whom correspondence should be addressed: Dept. of Molecular Internal Medicine, Medical Polyclinic, University of Wuerzburg, Roentgenring 11, 97070 Wuerzburg, Germany. Tel.: 49-931-201-71000; Fax: 49-931-201-71070; E-mail: harald.wajant{at}mail.uni-wuerzburg.de.

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