Regulated intramembrane proteolysis of the interleukin-1 receptor II by α-, β-, and γ-secretase
Regulated intramembrane proteolysis of the interleukin-1 receptor II by α-, β-, and γ-secretase
复制标题
DOI：
10.1074/jbc.m700356200
复制
发表时间：
2007-04-20
影响因子：
4.8
通讯作者：
Lichtenthaler, Stefan F.
中科院分区：
文献类型：
--
作者：
Kuhn, Peer-Hendrik;Marjaux, Els;Lichtenthaler, Stefan F.
淀粉样前体蛋白（APP）的胞外结构域脱落和膜内蛋白水解参与阿尔茨海默病（AD）的发病机制。另一种膜蛋白白细胞介素-1受体II（IL-1R2）的蛋白水解加工和分泌增加也与AD的发病机制有关。IL-1R2是一种诱饵受体，可以限制IL-1在大脑中的有害作用。目前，IL-1R2的蛋白水解加工仍知之甚少。在这里，我们表明，IL-1R2可以以类似于APP的方式进行蛋白水解加工。IL-1R2在人胚肾293细胞中表达，首先经历胞外域脱落的α-分泌酶样的方式，导致分泌的IL-1R2胞外域和IL-1R2的C-末端片段的产生。该片段通过γ-分泌酶进行进一步的膜内蛋白水解，导致IL-1R2的可溶性胞内结构域的产生。IL-1R2的膜内裂解被γ-分泌酶的高度特异性抑制剂废除，并且在γ-分泌酶活性缺陷的小鼠胚胎成纤维细胞中不存在。令人惊讶的是，γ-分泌酶BACE1及其同源物BACE2增加IL-1R2分泌，导致C-末端片段与α-分泌酶样切割产生的片段几乎相同。这表明这两种蛋白酶可能作为替代的γ-分泌酶样蛋白酶起作用。重要的是，BACE1和BACE2不切割其他几种膜蛋白，这表明这两种蛋白酶不有助于一般的膜蛋白周转，而只切割特定的蛋白质。这项研究揭示了IL-1R2和APP的类似蛋白水解加工，并可能为AD中观察到的IL-1R2分泌增加提供解释。
Ectodomain shedding and intramembrane proteolysis of the amyloid precursor protein ( APP) by alpha-, beta- and gamma-secretase are involved in the pathogenesis of Alzheimer disease ( AD). Increased proteolytic processing and secretion of another membrane protein, the interleukin-1 receptor II ( IL-1R2), have also been linked to the pathogenesis of AD. IL-1R2 is a decoy receptor that may limit detrimental effects of IL-1 in the brain. At present, the proteolytic processing of IL-1R2 remains little understood. Here we show that IL-1R2 can be proteolytically processed in a manner similar to APP. IL-1R2 expressed in human embryonic kidney 293 cells first undergoes ectodomain shedding in an alpha-secretase-like manner, resulting in secretion of the IL-1R2 ectodomain and the generation of an IL-1R2 C-terminal fragment. This fragment undergoes further intramembrane proteolysis by gamma-secretase, leading to the generation of the soluble intracellular domain of IL-1R2. Intramembrane cleavage of IL-1R2 was abolished by a highly specific inhibitor of gamma-secretase and was absent in mouse embryonic fibroblasts deficient in gamma-secretase activity. Surprisingly, the gamma-secretase BACE1 and its homolog BACE2 increased IL-1R2 secretion resulting in C-terminal fragments nearly identical to the ones generated by the alpha-secretase-like cleavage. This suggests that both proteases may act as alternative gamma-secretase-like proteases. Importantly, BACE1 and BACE2 did not cleave several other membrane proteins, demonstrating that both proteases do not contribute to general membrane protein turnover but only cleave specific proteins. This study reveals a similar proteolytic processing of IL-1R2 and APP and may provide an explanation for the increased IL-1R2 secretion observed in AD.