Pseudomonas aeruginosa elastase disables proteinase-activated receptor 2 in respiratory epithelial cells
Pseudomonas aeruginosa elastase disables proteinase-activated receptor 2 in respiratory epithelial cells
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DOI：
10.1165/rcmb.2004-0274oc
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发表时间：
2005-05-01
影响因子：
6.4
通讯作者：
Chignard, M
中科院分区：
文献类型：
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作者：
Dulon, S;Leduc, D;Chignard, M
铜绿假单胞菌是囊性纤维化（CF）患者的主要肺部病原体，分泌一种有助于细菌致病性的弹性蛋白溶解性金属蛋白酶（EPa）。参与肺先天防御的蛋白酶激活受体2（PAR 2）通过其细胞外N-末端结构域的切割而被激活，从而暴露出以SLIGKV开始的新的N-末端序列，其结合分子内并激活PAR 2。我们发现，EPa裂解的N-末端结构域PAR 2从细胞表面不触发受体encocytosis胰蛋白酶。如通过测量胞质钙以及前列腺素E-2和白细胞介素-8的产生所评估的，这种切割不激活PAR 2，而是解除受体的武装，以便随后被胰蛋白酶激活，而不是被合成的受体激活肽激活，SLIGKV-NH 2-通过EPa对代表N-末端切割的合成肽进行蛋白水解/人或大鼠PAR 2的激活序列表明，由EPa活性引起的裂解不会产生受体激活的栓系配体，但会通过激活蛋白酶解除PAR 2对任何进一步激活蛋白水解的武装。我们的数据表明，病原体衍生的蛋白酶如EPa可以潜在地沉默呼吸道中PAR 2的功能，从而改变宿主的先天防御机制和呼吸功能，从而有助于在疾病如CF的发病机制。
Pseudomonas aeruginosa, a major lung pathogen in cystic fibrosis (CF) patients, secretes an elastolytic metalloproteinase (EPa) contributing to bacterial pathogenicity. Proteinase-activated receptor 2 (PAR2), implicated in the pulmonary innate defense, is activated by the cleavage of its extracellular N-terminal domain, unmasking a new N-terminal sequence starting with SLIGKV, which binds intramolecularly and activates PAR2. We show that EPa cleaves the N-terminal domain of PAR2 from the cell surface without triggering receptor enclocytosis as trypsin does. As evaluated by measurements of cytosolic calcium as well as prostaglandin E-2 and interleukin-8 production, this cleavage does not activate PAR2, but rather disarms the receptor for subsequent activation by trypsin, but not by the synthetic receptor-activating peptide, SLIGKV-NH2- Proteolysis by EPa of synthetic peptides representing the N-terminal cleavage/activation sequences of either human or rat PAR2 indicates that cleavages resulting from EPa activity would not produce receptor-activating tethered ligands, but would disarm PAR2 in regard to any further activating proteolysis by activating proteinases. Our data indicate that a pathogen-derived proteinase like EPa can potentially silence the function of PAR2 in the respiratory tract, thereby altering the host innate defense mechanisms and respiratory functions, and thus contributing to pathogenesis in the setting of a disease like CF.