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Mechanism of Apoptosis Induction by Bacterial Proteases and Its Implication for Bacterial Pathogenesis.

细菌蛋白酶诱导细胞凋亡的机制及其对细菌发病机制的意义。

基本信息

批准号：
17590395
负责人：
TAMURA Fumio
金额：
$ 1.73万
依托单位：
Kumamoto university
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590395/
关键词：
Bacterial Portease Apoptosis a2-macrogrobulin MMP

项目摘要

Recently it was shown that streptococcal pyrogenic exotoxin B (SpeB), a thiol protease derived from group A Streptococcus (GAS) could cause an increase in apoptotic cell death. The present study is aimed to clarify the mechanism of apoptosis induced by a variety of bacterial proteases. When human monocyte- like U937 cells were treated with SpeB, Serratiamarcescens 56kDa protease, or Pseudomonas aeruginosa elastase, all these bacterial proteases induced apoptosis in U937 cells. Serratial protease was internalized by the cells in culture as a complex form with α2-macroglobulin (a2-M) via α2-M receptor, which resulted in apoptosis. Furthermore, expressions of Bcl-2, c-lAP1 and hsp70, which were anti-apoptotic proteins, were investigated by Western blot analysis after treatment of U937 cells with serratial protease. Serratial protease degraded c-IAP1 protein more selectively than others intracellular proteins. We previously reported that some bacterial proteases could activate human MMPs, which may play important roles in tissue degeneration, and in the present study, SpeB also was confirmed activation of MMPs. We investigated whether SpeB-activatedMMPcouldprocessTNF-a andFasligandfromcellmembranetocause apoptotic cell death. SpeB activated with proMM P-9, and soluble TN F-a and Fas ligand were released from culture cells by this activated MMP-9. SpeB-dependent induction of extensive apoptosis and its related proapoptotic molecules, e.g., soluble TNF-a, Fas ligand, and MMPs, was evident in a murine model of severe GAS infections. These results suggested that bacterial proteases induce apoptotic cell death either via α2-M receptor, or via activation of MMPs.

最近研究表明，链球菌致热外毒素B（SpeB），一种来源于A组链球菌（GAS）的巯基蛋白酶，可引起细胞凋亡的增加。本研究旨在阐明多种细菌蛋白酶诱导细胞凋亡的机制。当用SpeB、粘质沙雷氏菌56 kDa蛋白酶或铜绿假单胞菌弹性蛋白酶处理人单核细胞样U937细胞时，所有这些细菌蛋白酶都诱导U937细胞凋亡。Serratial蛋白酶与α2-巨球蛋白（α 2-M）通过α2-M受体以复合物形式被细胞内化，导致细胞凋亡。Western blot检测Serratial蛋白酶处理U937细胞后Bcl-2、c-IAP 1和hsp 70蛋白的表达。锯齿蛋白酶对c-IAP 1蛋白的降解选择性强于其它胞内蛋白。我们以前报道过一些细菌蛋白酶可以激活人的MMPs，这可能在组织变性中起重要作用，并且在本研究中，SpeB也被证实激活MMPs。我们研究了SpeB激活的MMP是否能处理TNF-α和Fas配体引起细胞凋亡。用proMMP-9激活SpeB，并且通过这种激活的MMP-9从培养细胞释放可溶性TNF-α和Fas配体。SpeB依赖性诱导广泛的凋亡及其相关的促凋亡分子，例如，可溶性TNF-α、Fas配体和MMP在严重GAS感染的鼠模型中是明显的。这些结果表明，细菌蛋白酶通过α2-M受体或通过激活MMPs诱导细胞凋亡。