The low affinity IgE receptor (CD23) is cleaved by the metalloproteinase ADAM10
The low affinity IgE receptor (CD23) is cleaved by the metalloproteinase ADAM10
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DOI：
10.1074/jbc.m608414200
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发表时间：
2007-05-18
影响因子：
4.8
通讯作者：
Werb, Zena
中科院分区：
文献类型：
--
作者：
Lemieux, George A.;Blumenkron, Fernando;Werb, Zena
低亲和力 IgE 受体 Fc epsilon RII (CD23) 既是 IgE 合成的正调节因子，又是负调节因子。将膜结合形式的 CD23 转化为可溶性物质 (sCD23) 的蛋白酶活性是 CD23 功能的重要调节剂，并且可能是控制过敏和炎症的重要治疗靶点。我们已经表征了 ADAM（一种解整合素和金属蛋白酶）10 对人 CD23 的催化活性。我们发现 ADAM10 有效催化来自 CD23 主链中两个不同切割位点的肽的切割。金属蛋白酶的组织抑制剂和 ADAM10 的特定前结构域抑制剂会干扰人白血病细胞系以及人 B 细胞原代培养物中内源产生的 CD23 的释放。 ADAM10 突变型金属蛋白酶缺陷构建体的表达部分抑制了 sCD23 的产生。同样，ADAM10 的小抑制性 RNA 敲低部分抑制了 CD23 的释放，并导致膜结合形式的 CD23 在细胞上积累。 ADAM10 有助于 CD23 脱落，因此可被视为治疗过敏性疾病的潜在治疗靶点。
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.