Cytoprotective roles of ERK and Akt in endoplasmic reticulum stress triggered by subtilase cytotoxin.
Cytoprotective roles of ERK and Akt in endoplasmic reticulum stress triggered by subtilase cytotoxin.
复制标题
DOI：
10.1016/j.bbrc.2011.06.078
复制
发表时间：
2011-07
影响因子：
3.1
通讯作者：
Tian Tian-Tian;Yang Zhao;S. Nakajima;Tao Huang;Jian Yao;A. Paton;J. Paton;M. Kitamura
中科院分区：
文献类型：
--
作者：
Tian Tian-Tian;Yang Zhao;S. Nakajima;Tao Huang;Jian Yao;A. Paton;J. Paton;M. Kitamura
枯草酶细胞毒素（SubAB）是由志贺产毒大肠杆菌产生的一种独特的ab5毒素家族的原型。最近的报道揭示了SubAB触发的促凋亡途径，而其抗凋亡信号尚未阐明。在本研究中，我们研究了SubAB引发的促生存信号，特别是细胞外信号调节激酶（ERK）和Akt。我们发现SubAB激活了ERK和Akt，抑制单个激酶会增强SubAB引发的细胞凋亡。SubAB诱导内质网（ER）应激，其他内质网应激诱导剂模仿SubAB对ERK和Akt的刺激作用。内质网应激的减弱减少了subab诱导的这些激酶的磷酸化，表明参与了未折叠蛋白反应（UPR）。SubAB诱导蛋白激酶样ER激酶（PERK）的激活和真核翻译起始因子2α (eIF2α)的磷酸化，而salubrinal磷酸化eIF2α引起ERK和Akt的激活，从而导致细胞存活。PERK的显性阴性抑制增强了subab诱导的细胞凋亡，降低了ERK和Akt的磷酸化。此外，eIF2α的抗凋亡作用可通过抑制ERK和Akt而明显逆转。这些结果表明，ERK和Akt在subab触发的内质网应激介导的细胞凋亡中具有细胞保护作用。
Subtilase cytotoxin (SubAB) is the prototype of a distinct AB5toxin family produced by Shiga toxigenic Escherichia coli. Recent reports disclosed pro-apoptotic pathways triggered by SubAB, whereas its anti-apoptotic signals have not been elucidated. In the present study, we investigated pro-survival signaling elicited by SubAB, especially focusing on extracellular signal-regulated kinase (ERK) and Akt. We found that SubAB activated ERK and Akt, and inhibition of individual kinases enhanced SubAB-triggered apoptosis. SubAB induced endoplasmic reticulum (ER) stress, and other ER stress inducers mimicked the stimulatory effects of SubAB on ERK and Akt. Attenuation of ER stress reduced SubAB-induced phosphorylation of these kinases, suggesting involvement of the unfolded protein response (UPR). SubAB induced activation of protein kinase-like ER kinase (PERK) and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), and phosphorylation of eIF2α by salubrinal caused activation of ERK and Akt, leading to cell survival. Dominant-negative inhibition of PERK enhanced SubAB-induced apoptosis and reduced phosphorylation of ERK and Akt. Furthermore, the anti-apoptotic effect of eIF2α was significantly reversed by inhibition of ERK and Akt. These results suggest cytoprotective roles of ERK and Akt in SubAB-triggered, ER stress-mediated apoptosis.