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J. Biol. Chem., Vol. 279, Issue 52, 54248-54257, December 24, 2004

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Inhibition of NF-B Activation by Peptides Targeting NF-B Essential Modulator (NEMO) Oligomerization^*

Fabrice Agou, Gilles Courtois¶||, Jeanne Chiaravalli, Françoise Baleux**, Yves-Marie Coïc**, François Traincard, Alain Israël¶, and Michel Véron

From the Unité de Régulation Enzymatique des Activités Cellulaires, CNRS URA 2185, ^¶Unité de Biologie Moléculaire de l'Expression Génique, CNRS URA 2582, and ^**Unité de Chimie Organique, CNRS URA 2128, Institut Pasteur, 25/28 rue du Dr. Roux 75724 Paris cedex 15 France

NF-B essential modulator/IKK- (NEMO/IKK-) plays a key role in the activation of the NF-B pathway in response to proinflammatory stimuli. Previous studies suggested that the signal-dependent activation of the IKK complex involves the trimerization of NEMO. The minimal oligomerization domain of this protein consists of two coiled-coil subdomains named Coiled-coil 2 (CC2) and leucine zipper (LZ) (Agou, F., Traincard, F., Vinolo, E., Courtois, G., Yamaoka, S., Israel, A., and Veron, M. (2004) J. Biol. Chem. 279, 27861–27869). To search for drugs inhibiting NF-B activation, we have rationally designed cell-permeable peptides corresponding to the CC2 and LZ subdomains that mimic the contact areas between NEMO subunits. The peptides were tagged with the Antennapedia/Penetratin motif and delivered to cells prior to stimulation with lipopolysaccharide. Peptide transduction was monitored by fluorescence-activated cell sorter, and their effect on lipopolysaccharide-induced NF-B activation was quantified using an NF-B-dependent -galactosidase assay in stably transfected pre-B 70Z/3 lymphocytes. We show that the peptides corresponding to the LZ and CC2 subdomains inhibit NF-B activation with an IC₅₀ in the µM range. Control peptides, including mutated CC2 and LZ peptides and a heterologous coiled-coil peptide, had no inhibitory effect. The designed peptides are able to induce cell death in human retinoblastoma Y79 cells exhibiting constitutive NF-B activity. Our results provide the "proof of concept" for a new and promising strategy for the inhibition of NF-B pathway activation through targeting the oligomerization state of the NEMO protein.

Received for publication, June 9, 2004 , and in revised form, October 1, 2004.

^* This work was supported in by grants from "the Association pour la Recherche sur le Cancer" (ARC Grant number 5795), the Ligue Nationale contre le Cancer (équipe labelisée) (to A. I.), and the Direction de la Valorisation et des Partenariats Industriels at the Pasteur Institut. 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.

^|| Present address: INSERM U532, Hôpital Saint-Louis, 75475 Paris cedex France.

To whom correspondence should be addressed. Tel.: 33-1-44-38-95-69; Fax: 33-1-45-68-83-99; E-mail: fagou{at}pasteur.fr.

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