Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Aβ-like peptide
Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Aβ-like peptide
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DOI：
10.1074/jbc.m206872200
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发表时间：
2002-11-22
影响因子：
4.8
通讯作者：
Haass, C
中科院分区：
文献类型：
--
作者：
Lammich, S;Okochi, M;Haass, C
阿尔茨海默病 (AD) 相关的 γ-分泌酶是一种早老素 (PS) 依赖性蛋白水解活性，参与 β-淀粉样前体蛋白、Notch、LDL 受体相关蛋白、E-钙粘蛋白和 ErbB-4 的膜内裂解。这种切割产生相应的细胞内结构域 (ICD)，这是 Notch 和可能的 ErbB-4、β-淀粉样前体蛋白、E-钙粘蛋白和 LDL 受体相关蛋白的核信号传导所必需的。我们现在研究了 CD44，一种细胞表面粘附分子，它也会经历膜内裂解以释放其 ICD。我们证明这种裂解需要 PS 依赖性的 γ 分泌酶活性。功能丧失的 PS1 突变、PS1/PS2 敲除以及两种独立且高度特异性的 γ 分泌酶抑制剂可消除这种裂解。令人惊讶的是，与淀粉样β-肽（Abeta）类似的小肽是通过CD44跨膜区中部的额外切割产生的。与 Abeta 一样，这些 CD44 β 肽以 PS 依赖性方式生成。因此，这些发现表明 PS 蛋白介导的双重膜内裂解机制。核信号传导以及剩余跨膜结构域的去除需要双重切割机制，这是 PS 在膜蛋白代谢中的一般功能。
Alzheimer's disease (AD)-associated gamma-secretase is a presenilin (PS)-dependent proteolytic activity involved in the intramembraneous cleavage of the beta-amyloid precursor protein, Notch, LDL receptor-related protein, E-cadherin, and ErbB-4. This cut produces the corresponding intracellular domains (ICD), which are required for nuclear signaling of Notch and probably ErbB-4, the beta-amyloid precursor protein, E-cadherin, and the LDL receptor-related protein as well. We have now investigated CD44, a cell surface adhesion molecule, which also undergoes an intramembraneous cleavage to liberate its ICD. We demonstrate that this cleavage requires a PS-dependent gamma-secretase activity. A loss-of-function PS1 mutation, a PS1/PS2 knockout, as well as two independent and highly specific gamma-secretase inhibitors, abolish this cleavage. Surprisingly, small peptides similar to the amyloid beta-peptide (Abeta) are generated by an additional cut in the middle of the transmembrane region of CD44. Like Abeta, these CD44 beta-peptides are generated in a PS-dependent manner. These findings therefore suggest a dual intramembraneous cleavage mechanism mediated by PS proteins. The dual cleavage mechanism is required for nuclear signaling as well as removal of remaining transmembrane domains, a general function of PS in membrane protein metabolism.