Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis
Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis
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DOI：
10.1084/jem.20171438
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发表时间：
2019-04-01
影响因子：
15.3
通讯作者：
Schroeder, Bernd
中科院分区：
文献类型：
--
作者：
Mentrup, Torben;Theodorou, Kosta;Schroeder, Bernd
凝集素样氧化低密度脂蛋白受体1（LOX-1）在动脉粥样硬化的发展中起关键作用。LOX-1通过介导氧化LDL的摄取和诱导促动脉粥样硬化信号传导促进内皮活化和功能障碍。然而，对LOX-1介导的反应的调节剂知之甚少。在这里，我们表明LOX-1的功能是由蛋白水解控制的。金属蛋白酶ADAM 10的胞外结构域脱落和溶酶体降解产生膜结合的N-末端片段（NTFs），我们将其鉴定为膜内蛋白酶信号肽肽酶样2a和B（SPPL 2a/B）的新型底物。SPPL 2a/B控制细胞LOX-1 NTF水平，其在通过其跨膜结构域自我缔合后，可以以配体非依赖性方式激活MAP激酶。这导致几种促动脉粥样硬化和促纤维化靶点的上调，包括ICAM-1和结缔组织生长因子CTGF。因此，SPPL 2a/b缺陷小鼠，积累LOX-1 NTFs，发展更大和更先进的动脉粥样硬化斑块比对照组。这将SPPL 2a/B的膜内蛋白水解鉴定为通过LOX-1信号传导的负调节的新的动脉粥样硬化保护机制。
The lectin-like oxidized LDL receptor 1 (LOX-1) is a key player in the development of atherosclerosis. LOX-1 promotes endothelial activation and dysfunction by mediating uptake of oxidized LDL and inducing pro-atherogenic signaling. However, little is known about modulators of LOX-1-mediated responses. Here, we show that the function of LOX-1 is controlled proteolytically. Ectodomain shedding by the metalloprotease ADAM10 and lysosomal degradation generate membrane-bound N-terminal fragments (NTFs), which we identified as novel substrates of the intramembrane proteases signal peptide peptidase-like 2a and b (SPPL2a/b). SPPL2a/b control cellular LOX-1 NTF levels which, following self-association via their transmembrane domain, can activate MAP kinases in a ligand-independent manner. This leads to an up-regulation of several pro-atherogenic and pro-fibrotic targets including ICAM-1 and the connective tissue growth factor CTGF. Consequently, SPPL2a/b-deficient mice, which accumulate LOX-1 NTFs, develop larger and more advanced atherosclerotic plaques than controls. This identifies intramembrane proteolysis by SPPL2a/b as a novel atheroprotective mechanism via negative regulation of LOX-1 signaling.