The type II transmembrane serine protease matriptase cleaves the amyloid precursor protein and reduces its processing to -amyloid peptide
The type II transmembrane serine protease matriptase cleaves the amyloid precursor protein and reduces its processing to -amyloid peptide
复制标题
DOI：
10.1074/jbc.m117.792911
复制
发表时间：
2017-12-15
影响因子：
4.8
通讯作者：
Lavoie, Christine
中科院分区：
文献类型：
--
作者：
Lanchec, Erwan;Desilets, Antoine;Lavoie, Christine
近年来的研究表明，除了典型的β-、β-和β-分泌酶外，许多蛋白酶也能切割淀粉样前体蛋白（APP）并调节β-淀粉样肽（A）的产生。此外，特定的APP亚型含有Kunitz蛋白酶抑制结构域，其调节丝氨酸蛋白酶的蛋白水解活性。这促使我们研究matriptase，II型跨膜丝氨酸蛋白酶家族的成员，在APP加工中的作用。使用定量RT-PCR，我们检测到间质蛋白酶mRNA在人脑的几个区域与富集的神经元。人类背外侧前额叶皮质的RNA测序数据显示，年轻个体中的间质蛋白酶RNA水平相对较高，而老年个体中检测到的水平较低。我们进一步证明了间质蛋白酶和APP直接相互作用，并且间质蛋白酶在体外和细胞中均在特定的精氨酸残基（Arg-102）处切割APP。该切割位点的定点（Arg-至-Ala）诱变废除了间质蛋白酶介导的APP加工。此外，我们观察到可溶性脱落的间质蛋白酶形式切割SH-SY 5 Y细胞中的内源性APP，并且这种切割显著降低APP加工至A40。总之，这项研究将间质蛋白酶鉴定为APP裂解酶，这种活性可能对A的丰度和阿尔茨海默病病理学产生重要影响。
Recent studies have reported that many proteases, besides the canonical -, -, and -secretases, cleave the amyloid precursor protein (APP) and modulate -amyloid (A) peptide production. Moreover, specific APP isoforms contain Kunitz protease-inhibitory domains, which regulate the proteolytic activity of serine proteases. This prompted us to investigate the role of matriptase, a member of the type II transmembrane serine protease family, in APP processing. Using quantitative RT-PCR, we detected matriptase mRNA in several regions of the human brain with an enrichment in neurons. RNA sequencing data of human dorsolateral prefrontal cortex revealed relatively high levels of matriptase RNA in young individuals, whereas lower levels were detected in older individuals. We further demonstrate that matriptase and APP directly interact with each other and that matriptase cleaves APP at a specific arginine residue (Arg-102) both in vitro and in cells. Site-directed (Arg-to-Ala) mutagenesis of this cleavage site abolished matriptase-mediated APP processing. Moreover, we observed that a soluble, shed matriptase form cleaves endogenous APP in SH-SY5Y cells and that this cleavage significantly reduces APP processing to A40. In summary, this study identifies matriptase as an APP-cleaving enzyme, an activity that could have important consequences for the abundance of A and in Alzheimer's disease pathology.