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J. Biol. Chem., Vol. 282, Issue 20, 14836-14844, May 18, 2007

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The Low Affinity IgE Receptor (CD23) Is Cleaved by the Metalloproteinase ADAM10^*

George A. Lemieux, Fernando Blumenkron, Nolan Yeung^¶, Pei Zhou^||, Jason Williams^**, Amrie C. Grammer, Robert Petrovich^**, Peter E. Lipsky, Marcia L. Moss¹, and Zena Werb²

From the Department of Anatomy and the Biomedical Sciences Program, University of California, San Francisco, California 94143, ^¶Cognosci, Research Triangle Park, North Carolina 27710, ^||Duke University Medical Center, Durham, North Carolina 27710, B Cell Biology Group, Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, Maryland 20892, ^**NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27710, and BioZyme Inc., Apex, North Carolina 27523

The low affinity IgE receptor, FcRII (CD23), is both a positive and negative regulator of IgE synthesis. The proteinase activity that converts the membrane-bound form of CD23 into a soluble species (sCD23) is an important regulator of the function of CD23 and may be an important therapeutic target for the control of allergy and inflammation. We have characterized the catalytic activity of ADAM (a disintegrin and metalloproteinase) 10 toward human CD23. We found that ADAM10 efficiently catalyzes the cleavage of peptides derived from two distinct cleavage sites in the CD23 backbone. Tissue inhibitors of metalloproteinases and a specific prodomain-based inhibitor of ADAM10 perturb the release of endogenously produced CD23 from human leukemia cell lines as well as primary cultures of human B-cells. Expression of a mutant metalloproteinase-deficient construct of ADAM10 partially inhibited the production of sCD23. Similarly, small inhibitory RNA knockdown of ADAM10 partially inhibited CD23 release and resulted in the accumulation of the membrane-bound form of CD23 on the cells. ADAM10 contributes to CD23 shedding and thus could be considered a potential therapeutic target for the treatment of allergic disease.

Received for publication, August 31, 2006 , and in revised form, March 13, 2007.

Addendum—While this manuscript was under review, an article was published (45) that found ADAM10 to be the major CD23 sheddase activity in mice.

^* This work was supported by National Institutes of Health Grants AI053194 and HL75602 (to Z. W.), the Sandler Family Sustaining Foundation, and Institutional National Research Service Award HL07731. 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 may be addressed: Biozyme Inc. Apex, NC 27523. Tel.: 919-362-1339; Fax: 919-362-1339; E-mail: mmoss{at}biozyme-inc.com. ² To whom correspondence may be addressed: Dept. of Anatomy, University of California, San Francisco, CA 94143-0452. Tel.: 415-476-4622; Fax: 415-476-4565; E-mail: zena.werb{at}ucsf.edu.

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