HtrA-mediated E-cadherin cleavage is limited to DegP and DegQ homologs expressed by gram-negative pathogens.
HtrA-mediated E-cadherin cleavage is limited to DegP and DegQ homologs expressed by gram-negative pathogens.
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DOI：
10.1186/s12964-016-0153-y
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发表时间：
2016-12-08
期刊：
影响因子：
--
通讯作者：
Wessler S
中科院分区：
文献类型：
--
作者：
Abfalter CM;Schubert M;Götz C;Schmidt TP;Posselt G;Wessler S
幽门螺杆菌（Helicobacter pylori，H. pylori）和空肠弯曲杆菌（C. jejuni）切割哺乳动物细胞粘附蛋白E-钙粘蛋白以打开细胞间粘附。多种细菌也表达HtrA/DegP同系物DegQ和/或DegS，其在结构和功能上显著不同。在革兰氏阴性病原体H. pylori、肠致病性大肠杆菌（EPEC）、肠道沙门氏菌亚种（Salmonella enterica subsp.）Enterica（S.鼠伤寒沙门氏菌（Y. Typhimurium）、小肠结肠炎耶尔森氏菌（Y. enterocolitica）。小肠结肠炎）和奇异变形杆菌（P. mirabilis），它们表达不同的HtrA组合。注释的野生型htrA/degP，degQ和degS基因克隆和蛋白水解失活突变体产生的丝氨酸丙氨酸交换的活性中心。所有HtrA变体过表达和纯化，以比较它们在酪蛋白酶谱和体外E-钙粘蛋白切割实验中的蛋白水解活性。上皮细胞的感染导致强烈的E-钙粘蛋白胞外结构域脱落，如通过全细胞裂解物中全长E-钙粘蛋白的损失和感染细胞的上清液中E-钙粘蛋白的可溶性90 kDa胞外结构域（NTF）的形成所反映的。重要的是，比较HtrA/DegP、DegQ和DegS蛋白的酪蛋白溶解活性和E-钙粘蛋白切割活性揭示了来自H. pylori、S.鼠伤寒（Typhimurium）、Y.小肠结肠炎菌、EPEC和奇异变形杆菌，但不是活化的DegS，在体外切割作为底物的E-钙粘蛋白。这些数据表明，E-钙粘蛋白裂解仅限于HtrA/DegP和DegQ蛋白，代表细菌发病机制中重要的普遍步骤。本文的在线版本（doi：10.1186/s12964-016-0153-y）包含补充材料，可供授权用户使用。
The serine proteases HtrA/DegP secreted by the human gastrointestinal pathogens Helicobacter pylori (H. pylori) and Campylobacter jejuni (C. jejuni) cleave the mammalian cell adhesion protein E-cadherin to open intercellular adhesions. A wide range of bacteria also expresses the HtrA/DegP homologs DegQ and/or DegS, which significantly differ in structure and function. E-cadherin shedding was investigated in infection experiments with the Gram-negative pathogens H. pylori, enteropathogenic Escherichia coli (EPEC), Salmonella enterica subsp. Enterica (S. Typhimurium), Yersinia enterocolitica (Y. enterocolitica), and Proteus mirabilis (P. mirabilis), which express different combinations of HtrAs. Annotated wild-type htrA/degP, degQ and degS genes were cloned and proteolytically inactive mutants were generated by a serine—to—alanine exchange in the active center. All HtrA variants were overexpressed and purified to compare their proteolytic activities in casein zymography and in vitro E-cadherin cleavage experiments. Infection of epithelial cells resulted in a strong E-cadherin ectodomain shedding as reflected by the loss of full length E-cadherin in whole cell lysates and formation of the soluble 90 kDa extracellular domain of E-cadherin (NTF) in the supernatants of infected cells. Importantly, comparing the caseinolytic and E-cadherin cleavage activities of HtrA/DegP, DegQ and DegS proteins revealed that DegP and DegQ homologs from H. pylori, S. Typhimurium, Y. enterocolitica, EPEC and P. mirabilis, but not activated DegS, cleaved E-cadherin as a substrate in vitro. These data indicate that E-cadherin cleavage is confined to HtrA/DegP and DegQ proteins representing an important prevalent step in bacterial pathogenesis. The online version of this article (doi:10.1186/s12964-016-0153-y) contains supplementary material, which is available to authorized users.
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