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J. Biol. Chem., Vol. 283, Issue 35, 23627-23635, August 29, 2008

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The Cleavage of Neutrophil Leukosialin (CD43) by Cathepsin G Releases Its Extracellular Domain and Triggers Its Intramembrane Proteolysis by Presenilin/-Secretase^*

Agnès Mambole¹, Dominique Baruch^¶, Patrick Nusbaum, Sylvain Bigot, Misa Suzuki^||, Philippe Lesavre, Minoru Fukuda^||, and Lise Halbwachs-Mecarelli²

From the INSERM U845, the Université René Descartes, 75015 Paris, ^¶INSERM U765, 75006 Paris, France, and the ^||Cancer Research Center, Burnham Institute for Medical Research, La Jolla, California 92037

The highly negatively charged membrane sialoglycoprotein leukosialin, CD43, is shed during neutrophil activation. This is generally thought to enhance cell adhesion. We here describe two novel consequences of this shedding, during neutrophil activation by phorbol esters or by chemoattractants after TNF- priming. CD43 proteolysis was investigated by Western blotting, using a polyclonal antibody to CD43 intracellular domain. Our data emphasize the importance of a juxtamembranous cleavage of about 50% of membrane CD43 molecules by cathepsin G. Indeed, it is inhibited by 1-antichymotrypsin and cathepsin G inhibitor I and is reproduced by exogenous purified cathepsin G. The resulting membrane-anchored C-terminal fragment, CD43-CTF, becomes susceptible to presenilin/-secretase, which releases CD43 intracytoplasmic domain: preincubation with three different -secretase inhibitors, before PMN treatment by agonists or by purified cathepsin G, results in the accumulation of CD43-CTF. Because CD43 binds E-selectin, we also investigated the effect of the soluble extracellular domain CD43s, released by cathepsin G juxtamembranous cleavage, on neutrophil adhesion to endothelial cells. A recombinant CD43s-Fc fusion protein inhibited neutrophil E selectindependent adhesion to endothelial cells under flow conditions, while it had no effect on neutrophil static adhesion. We thus propose that, in addition to its potential pro-adhesive role, CD43 proteolysis results in: (i) the release, by cathepsin G, of CD43 extracellular domain, able to inhibit the adhesion of flowing neutrophils on endothelial cells and thus to participate to the natural control of inflammation; (ii) the release and/or the clearance, by presenilin/-secretase, of CD43 intracellular domain, thereby regulating CD43-mediated signaling.

Received for publication, December 18, 2007 , and in revised form, June 9, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health NCI Grant CA 33000. This work was also supported in part by the Association pour l'Utilisation du Rein Artificiel AURA, Baxter, and Amgen. 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.

¹ Supported successively by a grant from the Association pour La Recherche sur la Polyarthrite and a grant from the Société Française d'Hématologie.

² To whom correspondence should be addressed: INSERM U 845, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France. Fax: 33-144-49-02-90; E-mail: lise.halbwachs{at}inserm.fr.

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