Neutrophil Elastase and Proteinase-3 Trigger G Protein-biased Signaling through Proteinase-activated Receptor-1 (PAR1)
Neutrophil Elastase and Proteinase-3 Trigger G Protein-biased Signaling through Proteinase-activated Receptor-1 (PAR1)
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DOI：
10.1074/jbc.m113.483123
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发表时间：
2013-11-15
影响因子：
4.8
通讯作者：
Hollenberg, Morley D.
中科院分区：
文献类型：
--
作者：
Mihara, Koichiro;Ramachandran, Rithwik;Hollenberg, Morley D.
背景：蛋白酶激活受体-1 （PAR1）是一种蛋白水解激活的G蛋白偶联受体。中性粒细胞衍生的酶可能调节PAR1信号。结果：中性粒细胞弹性酶和蛋白酶-3切割和激活PAR1信号，这与凝血酶触发的反应不同。中性粒细胞弹性酶和蛋白酶-3信号通过PAR1调节内皮细胞信号。结论：中性粒细胞酶是PAR1的G(i)偏向激动剂。意义：偏倚par1激活化合物可作为治疗心血管和炎症性疾病的药物。炎症部位释放的中性粒细胞蛋白酶可通过激活或解除蛋白酶激活受体（PARs）介导的信号转导影响组织功能。由于PAR1在大量中性粒细胞浸润的部位表达，我们假设中性粒细胞衍生的酶也可能调节PAR1信号传导。我们在这里报道了中性粒细胞弹性酶和蛋白酶-3在不同凝血酶切割位点切割人par1n末端。这种分裂导致凝血酶激活的钙信号通过PAR1解除。然而，中性粒细胞弹性酶和蛋白酶-3所揭示的独特的非规范系链配体，以及由这些新暴露的系链配体衍生的序列合成的肽，选择性地刺激par1介导的有丝分裂原激活的蛋白激酶激活。该信号被百日咳毒素阻断，暗示了G(i)触发的信号通路。我们得出结论，中性粒细胞蛋白酶触发偏倚的PAR1信号，我们描述了一组新的栓系配体，不同于凝血酶揭示的经典栓系配体。我们进一步证明了这种偏倚信号在调节内皮细胞屏障完整性中的作用。
Background: Proteinase-activated receptor-1 (PAR1) is a proteolytically activated G protein-coupled receptor. Neutrophil-derived enzymes might regulate PAR1 signaling. Results: Neutrophil elastase and proteinase-3 cleave and activate PAR1 signaling that is distinct from thrombin-triggered responses. Neutrophil elastase and proteinase-3 signaling through PAR1 modulates endothelial cell signaling. Conclusion: Neutrophil enzymes are G(i)-biased agonists for PAR1. Significance: Biased PAR1-activating compounds may prove of value as therapeutic agents to treat cardiovascular and inflammatory diseases.Neutrophil proteinases released at sites of inflammation can affect tissue function by either activating or disarming signal transduction mediated by proteinase-activated receptors (PARs). Because PAR1 is expressed at sites where abundant neutrophil infiltration occurs, we hypothesized that neutrophil-derived enzymes might also regulate PAR1 signaling. We report here that both neutrophil elastase and proteinase-3 cleave the human PAR1 N terminus at sites distinct from the thrombin cleavage site. This cleavage results in a disarming of thrombin-activated calcium signaling through PAR1. However, the distinct non-canonical tethered ligands unmasked by neutrophil elastase and proteinase-3, as well as synthetic peptides with sequences derived from these novel exposed tethered ligands, selectively stimulated PAR1-mediated mitogen-activated protein kinase activation. This signaling was blocked by pertussis toxin, implicating a G(i)-triggered signal pathway. We conclude that neutrophil proteinases trigger biased PAR1 signaling and we describe a novel set of tethered ligands that are distinct from the classical tethered ligand revealed by thrombin. We further demonstrate the function of this biased signaling in regulating endothelial cell barrier integrity.