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J. Biol. Chem., Vol. 281, Issue 9, 5780-5789, March 3, 2006

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A Novel Protease Inhibitor of the ₂-Macroglobulin Family Expressed in the Human Epidermis^*

Marie-Florence Galliano, Eve Toulza, Hélène Gallinaro, Nathalie Jonca, Akemi Ishida-Yamamoto, Guy Serre, and Marina Guerrin¹

From the UMR 5165, Epidermis Differentiation and Rheumatoid Autoimmunity, CNRS-Toulouse III University (IFR 30, INSERM-CNRS-Toulouse III University-CHU), 31073 Toulouse, France and the Department of Dermatology, Asahikawa Medical College, Asahikawa, 078-8510, Japan

In the course of a large scale analysis of late-expressed genes in the human epidermis, we identified a new member of the ₂-macroglobulin (2M) protease inhibitor family, A2ML1 (for ₂-macroglobulin-like 1). Like A2M and PZP, A2ML1 is located on chromosome 12p13.31. A2ML1 encodes a protein of 1454 amino acids, which fits the characteristics of 2Ms: 1) strong conservation in amino acid sequence including most of cysteine positions with 2M; 2) a putative central bait domain; 3) a typical thiol ester sequence. Northern blot and reverse transcriptase-PCR studies revealed a single 5-kb A2ML1 mRNA, mainly in the epidermis granular keratinocytes. A2ML1 is also transcribed in placenta, thymus, and testis. By Western blot analysis, 2ML1 is detected as a monomeric, 180-kDa protein in human epidermis. In vitro keratinocyte differentiation is associated with increased expression levels. By immunohistochemistry, 2ML1 was detected within keratinosomes in the granular layer of the epidermis, and as a secreted product in the extracellular space between the uppermost granular layer and the cornified layer. Recombinant 2ML1 displayed inhibitory activity toward chymotrypsin, papain, thermolysin, subtilisin A, and to a lesser extent, elastase but not trypsin. Incubation with chymotrypsin and the chymotrypsin-like kallikrein 7 protease indicated that 2ML1 binds covalently to these proteases, a feature shared with other members of the family. Therefore, 2ML1 is the first 2M family member detected in the epidermis. It may play an important role during desquamation by inhibiting extracellular proteases.

Received for publication, July 22, 2005 , and in revised form, November 18, 2005.

^* This work was supported in part by grants from the CNRS, Fonds Europeén de Développement Régional, and the "Société de Recherche Dermatologique." The immunoelectron microscopy work was partially supported by grants from the Ministry of Education, Culture, Sports, Science and Technology and the Minister of Health, Labor and Welfare of Japan (to A. L.-Y.). 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 To whom correspondence should be addressed: UDEAR UMR5165, 37 allées J. Guesde, 31073 Toulouse, France. Tel.: 33-5-61-14-59-44; Fax: 33-5-61-14-59-38; E-mail: mweber{at}udear.cnrs.fr.

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