Tang Bin, Li Qian, Zhao Xiu-hua, Wang Hai-guang, Li Na, Fang Yao, Wang Kun, Jia Yin-ping, Zhu Pan, Gu Jiang, Li Jing-xin, Jiao Yong-jun, Tong Wen-de, Wang Marissa, Zou Quan-ming, Zhu Feng-cai, Mao Xu-hu
a National Engineering Research Center for Immunobiological Products; Department of Microbiology and Biochemical Pharmacy; College of Pharmacy; Third Military Medical University ; Chongqing , China.
Autophagy. 2015;11(2):344-54. doi: 10.1080/15548627.2015.1023682.
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.
志贺毒素（Stxs）是一类细胞毒性蛋白家族，可导致血性腹泻、溶血尿毒综合征以及由痢疾志贺菌、大肠杆菌O157:H7和大肠杆菌O104:H4等细菌引起的中枢神经系统并发症。越来越多的证据表明，巨自噬（自噬）是志贺毒素诱导细胞死亡的关键因素。然而，相关机制尚不清楚。本研究表明，Stx2在人肠上皮细胞的培养系模型Caco-2细胞中诱导自噬性细胞死亡。使用3-甲基腺嘌呤和巴弗洛霉素A1等药理抑制剂抑制自噬，或使自噬基因ATG12或BECN1沉默，均可降低Stx2诱导的Caco-2细胞死亡。此外，在经Stx2处理的Caco-2细胞中存在大量内质网（ER）扩张的情况，并且由于DDIT3和NUPR1的存活候选物耗尽导致内质网应激受到抑制。这些过程导致了Stx2诱导的自噬和细胞死亡。最后，数据表明，伪激酶TRIB3介导的内质网应激时的DDIT3表达和AKT1去磷酸化是由Stx2触发的。因此，数据表明Stx2通过内质网应激途径在肠上皮细胞中引起自噬性细胞死亡。
