Subtilase cytotoxin produced by locus of enterocyte effacement-negative Shiga-toxigenic Escherichia coli induces stress granule formation.
Subtilase cytotoxin produced by locus of enterocyte effacement-negative Shiga-toxigenic Escherichia coli induces stress granule formation.
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DOI：
10.1111/cmi.12565
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发表时间：
2016-07
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
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枯草杆菌细胞毒素(SubAB)主要由肠上皮细胞消失区(Lee)阴性的产志贺菌毒素(STEC)菌株产生。SubAB裂解内质网(ER)伴侣Bip/GRP78，导致内质网应激的诱导。这种应激导致内质网应激感受器蛋白的激活，并诱导caspase依赖的细胞凋亡。我们发现SubAB可在多种细胞中诱导应激颗粒(SG)。本研究旨在探讨SubAB诱导SG形成的机制。在这里，我们证明了SubAB诱导的SG的形成是通过激活双链RNA激活的蛋白激酶(PKR)样的内质网激酶(PERK)来调节的。STEC O113：H21的培养上清液可显著诱导Caco 2细胞的SG，而亚AB基因敲除的STEC O113：H21培养上清液则无此作用。蛋白激酶C(PKC)激活剂佛波酯(PMA)和溶酶体抑制剂NH4Cl和氯喹可抑制SubAB诱导的SG的形成，而PKC和PKD抑制剂可促进这一过程。SubAB可降低PKD1的磷酸化水平。SiRNA缺失PKC、δ和PKD1后，促进了SG的形成。此外，死亡相关蛋白1(DAP1)的敲除增加了基础磷酸化PKD 1(S916)，并抑制了SubAB的SG形成。然而，在PMA处理的细胞中，内质网应激诱导剂thapsigargin所产生的SG不受抑制。我们的发现表明，SubAB诱导的SG的形成受PERK/DAP1信号通路的调控，该信号通路可能受PKCδ/PKD 1的调控，而不同于导致thapsigargin诱导的SG形成的信号转导途径。
Subtilase cytotoxin (SubAB) is mainly produced by locus of enterocyte effacement (LEE)-negative strains of Shiga-toxigenic Escherichia coli (STEC). SubAB cleaves an endoplasmic reticulum (ER) chaperone, BiP/Grp78, leading to induction of ER stress. This stress causes activation of ER stress sensor proteins and induction of caspase-dependent apoptosis. We found that SubAB induces stress granules (SG) in various cells. Aim of this study was to explore the mechanism by which SubAB induced SG formation. Here, we show that SubAB-induced SG formation is regulated by activation of double-stranded RNA-activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK). The culture supernatant of STEC O113:H21 dramatically induced SG in Caco2 cells, although subAB knockout STEC O113:H21 culture supernatant did not. Treatment with phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, and lysosomal inhibitors, NH4Cl and chloroquine, suppressed SubAB-induced SG formation, which was enhanced by PKC and PKD inhibitors. SubAB attenuated the level of PKD1 phosphorylation. Depletion of PKCδ and PKD1 by siRNA promoted SG formation in response to SubAB. Furthermore, death-associated protein 1 (DAP1) knockdown increased basal phospho-PKD1(S916) and suppressed SG formation by SubAB. However, SG formation by an ER stress inducer, Thapsigargin, was not inhibited in PMA-treated cells. Our findings show that SubAB-induced SG formation is regulated by the PERK/DAP1 signalling pathway, which may be modulated by PKCδ/PKD1, and different from the signal transduction pathway that results in Thapsigargin-induced SG formation.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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影响因子：
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