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J. Biol. Chem., Vol. 282, Issue 41, 29998-30004, October 12, 2007

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Annexin 1 Cleavage in Activated Neutrophils

A PIVOTAL ROLE FOR PROTEINASE 3^*

Linda Vong¹, Fulvio D'Acquisto¹, Magali Pederzoli-Ribeil², Luisa Lavagno, Roderick J. Flower, Véronique Witko-Sarsat³, and Mauro Perretti⁴

From the William Harvey Research Institute, Barts and The London, Charterhouse Square, London EC1M 6BQ, United Kingdom and INSERM U845 and Paris V University, Necker Hospital, 161 Rue de Sèvres, 75015 Paris, France

Annexin 1 is an anti-inflammatory protein that plays a key role in innate immunity by modulating the activation of several types of cells, including neutrophils. Here we have developed a cleavage assay using tagged annexin 1 and observed marked activity in the membrane fraction of activated neutrophils. A combination of inhibitors, transfected cells, and proteomic analyses allowed us to identify proteinase 3 as the main enzyme responsible for this cleavage in the N terminus region of the protein, at least in the context of neutrophil activation. Because annexin 1 is an important endogenous anti-inflammatory mediator, blocking its cleavage by proteinase 3 would augment its homeostatic pro-resolving actions and could represent an opportunity for innovative anti-inflammatory drug discovery.

Received for publication, April 4, 2007 , and in revised form, July 16, 2007.

^* This work was supported in part by the Research Advisory Board of Barts and the London (Ph.D. studentship to L. V.), the British Heart Foundation (Grant 06/153/22042), the Medical Research Council (to F. D. A.), the Arthritis Research Campaign UK (to M. P.), and Wellcome Trust (to R. J. F.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3 and supplemental references and experimental procedures.

¹ Both authors contributed equally to this work.

² Supported by Association de Recherche sur la Polyarthrite and Fondation pour la Recherche Médicale.

³ Supported by the Baxter Extramural Grant Program and by AMGEN.

⁴ To whom correspondence should be addressed. Tel.: 44-207-882-6065; Fax: 44-207-882-6076; E-mail: M.Perretti{at}qmul.ac.uk.

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