Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia.
Infect Immun. 2010 Nov;78(11):4691-6. doi: 10.1128/IAI.00801-10. Epub 2010 Aug 16.
Subtilase cytotoxin (SubAB) was first isolated from a Shiga toxigenic Escherichia coli (STEC) strain that was responsible for an outbreak of hemolytic-uremic syndrome and is the prototype of a new family of AB(5) cytotoxins. SubAB is a subtilase-like serine protease, and upon uptake by host cells, it is trafficked to the endoplasmic reticulum (ER), where it cleaves the essential ER chaperone BiP (GRP78) with high specificity. Previous work has shown that BiP cleavage by SubAB initiates ER stress-signaling pathways in host cells that eventuate in cell death associated with DNA fragmentation, a hallmark of apoptosis. The present study has investigated the role of the Bcl-2 protein family, which has been shown to regulate ER stress-induced apoptosis in other model systems. Examination of the cytotoxicity of SubAB for wild-type and bax(-/-)/bak(-/-) mouse embryonic fibroblasts and comparison of apoptotic markers in these cells revealed that SubAB cytotoxicity can be predominantly attributed to the activation of apoptotic pathways activated by Bax/Bak. The results of the present study further our understanding of the molecular mechanism whereby SubAB kills eukaryotic cells and contributes to STEC pathogenesis, in addition to consolidating the roles of Bcl-2 family members in the regulation of ER stress-induced apoptosis.
梭菌蛋白酶细胞毒素（SubAB）最初是从一株志贺毒素产生型大肠杆菌（STEC）菌株中分离出来的，该菌株是溶血性尿毒综合征爆发的病原体，也是一种新型 AB(5)细胞毒素的原型。SubAB 是一种类似于枯草杆菌蛋白酶的丝氨酸蛋白酶，在被宿主细胞摄取后，它会被运送到内质网（ER），在那里它以高特异性切割必需的 ER 伴侣蛋白 BiP（GRP78）。先前的工作表明，SubAB 切割 BiP 会引发宿主细胞中的 ER 应激信号通路，最终导致与 DNA 片段化相关的细胞死亡，这是细胞凋亡的一个标志。本研究探讨了 Bcl-2 蛋白家族的作用，该家族已被证明在其他模型系统中调节 ER 应激诱导的细胞凋亡。研究 SubAB 对野生型和 bax(-/-)/bak(-/-) 小鼠胚胎成纤维细胞的细胞毒性，并比较这些细胞中的凋亡标记物，结果表明 SubAB 的细胞毒性主要归因于 Bax/Bak 激活的凋亡途径的激活。本研究的结果进一步阐明了 SubAB 杀死真核细胞并促进 STEC 发病机制的分子机制，同时也巩固了 Bcl-2 家族成员在调节 ER 应激诱导的细胞凋亡中的作用。
