Shiga toxins induce autophagic cell death in intestinal epithelial cells via the endoplasmic reticulum stress pathway
Shiga toxins induce autophagic cell death in intestinal epithelial cells via the endoplasmic reticulum stress pathway
复制标题
志贺毒素通过内质网应激途径诱导肠上皮细胞自噬细胞死亡
DOI：
10.1080/15548627.2015.1023682
复制
发表时间：
2015-02-01
期刊：
影响因子：
13.3
通讯作者：
Mao, Xu-hu
中科院分区：
文献类型：
--
作者：
Tang, Bin;Li, Qian;Mao, Xu-hu
滋贺毒素（Stxs）是一个细胞毒性蛋白家族，其导致由细菌如志贺菌引起的血性腹泻、溶血性尿毒症综合征和中枢神经系统并发症的发展。Aesthacteriae、E. coliO 157：H7和E. coli O104：H4。越来越多的证据表明，巨自噬（自噬）是由Stxs诱导的细胞死亡的关键因素。然而，相关的机制尚不清楚。这项研究表明，Stx 2诱导Caco-2细胞（一种培养的人肠上皮细胞系模型）中的自噬性细胞死亡。使用药理学抑制剂如3-甲基腺嘌呤和巴弗洛霉素A1抑制自噬，或沉默自噬基因ATG 12或BECN 1降低了Stx 2诱导的Caco-2细胞死亡。此外，在Stx 2处理的Caco-2细胞中存在许多扩张的内质网（ER）的情况，以及由于DDIT 3和NUPR 1的可行候选物的耗尽而导致的ER应激的抑制。这些过程导致Stx 2诱导的自噬和细胞死亡。最后，数据显示，假激酶TRIB 3介导的DDIT 3表达和ER应激后AKT 1去磷酸化由Stx 2触发。因此，数据表明Stx 2通过肠上皮细胞中的ER应激途径引起自噬性细胞死亡。
Shiga toxins (Stxs) are a family of cytotoxic proteins that lead to the development of bloody diarrhea, hemolytic-uremic syndrome, and central nervous system complications caused by bacteria such as S. dysenteriae, E. coli O157:H7 and E. coli O104:H4. Increasing evidence indicates that macroautophagy (autophagy) is a key factor in the cell death induced by Stxs. However, the associated mechanisms are not yet clear. This study showed that Stx2 induces autophagic cell death in Caco-2 cells, a cultured line model of human enterocytes. Inhibition of autophagy using pharmacological inhibitors, such as 3-methyladenine and bafilomycin A1, or silencing of the autophagy genes ATG12 or BECN1 decreased the Stx2-induced death in Caco-2 cells. Furthermore, there were numerous instances of dilated endoplasmic reticulum (ER) in the Stx2-treated Caco-2 cells, and repression of ER stress due to the depletion of viable candidates of DDIT3 and NUPR1. These processes led to Stx2-induced autophagy and cell death. Finally, the data showed that the pseudokinase TRIB3-mediated DDIT3 expression and AKT1 dephosphorylation upon ER stress were triggered by Stx2. Thus, the data indicate that Stx2 causes autophagic cell death via the ER stress pathway in intestinal epithelial cells.