Endoplasmic reticulum stress contributes to Helicobacter pylori VacA-induced apoptosis.
Endoplasmic reticulum stress contributes to Helicobacter pylori VacA-induced apoptosis.
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DOI：
10.1371/journal.pone.0082322
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Nakao K
中科院分区：
文献类型：
--
作者：
Akazawa Y;Isomoto H;Matsushima K;Kanda T;Minami H;Yamaghchi N;Taura N;Shiozawa K;Ohnita K;Takeshima F;Nakano M;Moss J;Hirayama T;Nakao K
空泡毒素A(VacA)是幽门螺杆菌产生的重要毒力因子之一。VacA可诱导细胞凋亡，氨可加强这一作用。VacA还通过线粒体损伤通过尚未完全确定的信号通路导致细胞死亡。我们的目的是确定内质网(ER)应激是否与VacA诱导的线粒体功能障碍和细胞凋亡有关。我们发现，内质网应激诱导细胞凋亡的关键信号蛋白C/EBP同源蛋白(CHOP)在VacA与胃上皮细胞孵育后转录上调。与氯化铵共同孵育可显著提高VacA诱导CHOP的效果。在氯化铵存在下与VacA孵育后，也观察到了真核细胞起始因子2(EIF2)-α的磷酸化，这种磷酸化发生在内质网应激传感器PKR样受体定位的eIF2-α激酶(PERK)的下游，并调节CHOP的表达。SiRNA抑制CHOP可抑制VacA诱导的细胞凋亡。进一步的研究表明，siRNA沉默perk基因可减弱VacA介导的eIF2-α的磷酸化、CHOP诱导、BH3-Only蛋白Bim的表达和Bax的激活，以及VacA和氯化铵诱导的细胞死亡，提示内质网应激可能导致VacA诱导的毒性过程中线粒体功能障碍。在幽门螺杆菌感染的人胃粘膜中也观察到内质网应激的激活和BH3-Only蛋白的上调。总之，这项研究揭示了VacA诱导的胃上皮细胞凋亡与幽门螺杆菌阳性胃粘膜内质网应激激活之间的可能联系。
Vacuolating cytotoxin A (VacA) is one of the important virulence factors produced by H. pylori. VacA induces apoptotic cell death, which is potentiated by ammonia. VacA also causes cell death by mitochondrial damage, via signaling pathways that are not fully defined. Our aim was to determine whether endoplasmic reticulum (ER) stress is associated with VacA-induced mitochondrial dysfunction and apoptosis. We found that C/EBP homologous protein (CHOP), a key signaling protein of ER stress-induced apoptosis, was transcriptionally up-regulated following incubation of gastric epithelial cells with VacA. The effect of VacA on CHOP induction was significantly enhanced by co-incubation with ammonium chloride. Phosphorylation of eukaryotic initiation factor 2 (eIF2)-alpha, which is known to occur downstream of the ER stress sensor PKR-like ER-localized eIF2-alpha kinase (PERK) and to regulate CHOP expression, was also observed following incubation with VacA in the presence of ammonium chloride. Knockdown of CHOP by siRNA resulted in inhibition of VacA-induced apoptosis. Further studies showed that silencing of the PERK gene with siRNA attenuated VacA-mediated phosphorylation of eIF2-alpha, CHOP induction, expression of BH3-only protein Bim and Bax activation, and cell death induced by VacA with ammonium chloride, indicating that ER stress may lead to mitochondrial dysfunction during VacA-induced toxicity. Activation of ER stress and up-regulation of BH3-only proteins were also observed in human H. pylori-infected gastric mucosa. Collectively, this study reveals a possible association between VacA-induced apoptosis in gastric epithelial cells, and activation of ER stress in H. pylori-positive gastric mucosa.
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影响因子：
5.7
作者：
Kim IJ;Blanke SR
通讯作者：
Blanke SR
影响因子：
25.7
作者：
Akazawa Y;Cazanave S;Mott JL;Elmi N;Bronk SF;Kohno S;Charlton MR;Gores GJ
通讯作者：
Gores GJ
影响因子：
3.1
作者：
Matsumoto, Ayako;Isomoto, Hajime;Kohno, Shigeru
通讯作者：
Kohno, Shigeru
影响因子：
3.1
作者：
Lee, Moo-Seung;Cherla, Rama P.;Tesh, Vernon L.
通讯作者：
Tesh, Vernon L.
DOI：
10.1083/jcb.153.5.1011
发表时间：
2001-05-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Novoa I;Zeng H;Harding HP;Ron D
通讯作者：
Ron D