A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10)
A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10)
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DOI：
10.1096/fj.08-109033
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发表时间：
2008-10-01
期刊：
影响因子：
4.8
通讯作者：
Bianchi, Marco E.
中科院分区：
文献类型：
--
作者：
Raucci, Angela;Cugusi, Simona;Bianchi, Marco E.
晚期糖基化终末产物 (RAGE) 受体介导对细胞危险和压力的反应。当与多种配体（包括晚期糖基化终产物、S100/钙颗粒蛋白家族的某些成员、细胞外高迁移率族盒 1、整合素 Mac-1、淀粉样蛋白（β 肽和原纤维）结合时，RAGE 会激活负责急性和慢性炎症的程序。因此，RAGE 还参与癌症进展、糖尿病、动脉粥样硬化和阿尔茨海默氏病。RAGE 有多种衍生自替代品的亚型剪接，包括称为内源性分泌型 RAGE (esRAGE) 的可溶性形式，我们在此表明，大多数可溶性 RAGE，无论是由细胞系产生还是存在于人血液中，都不会被抗 esRAGE 抗体识别。用全长 RAGE cDNA 转染的细胞因此不表达 esRAGE，产生一种可溶性 RAGE，即裂解的 RAGE (cRAGE)。通过筛选化学抑制剂和转基因小鼠胚胎成纤维细胞 (MEF)，我们发现脱落酶 ADAM10 是一种负责 RAGE 裂解的膜蛋白酶，其配体 HMGB1 的结合可促进 RAGE 脱落，但我们的数据并没有反驳高水平可溶性 RAGE 可以预防慢性炎症的解释，而是表明它们与高水平的持续炎症相关。
The receptor for advanced glycation endproducts (RAGE) mediates responses to cell danger and stress. When bound by its many ligands (which include advanced glycation endproducts, certain members of the S100/calgranulin family, extracellular high-mobility group box 1, the integrin Mac-1, amyloid (beta-peptide and fibrils), RAGE activates programs responsible for acute and chronic inflammation. RAGE is therefore also involved in cancer progression, diabetes, atherosclerosis, and Alzheimer's disease. RAGE has several isoforms deriving from alternative splicing, including a soluble form called endogenous secretory RAGE (esRAGE). We show here that most soluble RAGE, either produced by cell lines or present in human blood, is not recognized by an anti-esRAGE antibody. Cells transfected with the cDNA for full-length RAGE, and thus not expressing esRAGE, produce a form of soluble RAGE, cleaved RAGE (cRAGE) that derives from proteolytic cleavage of the membrane-bound molecules and acts as a decoy receptor. By screening chemical inhibitors and genetically modified mouse embryonic fibroblasts (MEFs), we identify the sheddase ADAM10 as a membrane protease responsible for RAGE cleavage. Binding of its ligand HMGB1 promotes RAGE shedding. Our data do not disprove the interpretation that high levels of soluble forms of RAGE protect against chronic inflammation, but rather suggest that they correlate with high levels of ongoing inflammation.