The low affinity IgE receptor (CD23) is cleaved by the metalloproteinase ADAM10

被引:76
作者
Lemieux, George A.
Blumenkron, Fernando
Yeung, Nolan
Zhou, Pei
Williams, Jason
Grammer, Amrie C.
Petrovich, Robert
Lipsky, Peter E.
Moss, Marcia L. [1 ]
Werb, Zena
机构
[1] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Program Biomed Sci, San Francisco, CA 94143 USA
[3] Cognosci, Durham, NC 27710 USA
[4] Duke Univ, Med Ctr, Durham, NC 27710 USA
[5] NIAMS, B Cell Biol Grp, Autoimmun Branch, NIH, Bethesda, MD 20892 USA
[6] NIEHS, NIH, Durham, NC 27710 USA
[7] BioZyme Inc, Apex, NC 27523 USA
关键词
D O I
10.1074/jbc.M608414200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The low affinity IgE receptor, Fc epsilon RII (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.
引用
收藏
页码:14836 / 14844
页数:9
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