Subtilase cytotoxin, produced by Shiga-toxigenic Escherichia coli, transiently inhibits protein synthesis of Vero cells via degradation of BiP and induces cell cycle arrest at G1 by downregulation of cyclin D1
Subtilase cytotoxin, produced by Shiga-toxigenic Escherichia coli, transiently inhibits protein synthesis of Vero cells via degradation of BiP and induces cell cycle arrest at G1 by downregulation of cyclin D1
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DOI：
10.1111/j.1462-5822.2007.01094.x
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发表时间：
2008-04-01
影响因子：
3.4
通讯作者：
Noda, Masatoshi
中科院分区：
文献类型：
--
作者：
Morinaga, Naoko;Yahiro, Kinnosuke;Noda, Masatoshi
枯草杆菌酶细胞毒素（Subtilase cytotoxin，SubAB）是由志贺样大肠杆菌产生的AB（5）型毒素，对Vero细胞具有细胞毒性。SubAB B亚基与细胞表面的毒素受体结合，而A亚基是一种枯草杆菌酶样丝氨酸蛋白酶，其特异性切割伴侣BiP/Grp 78。如前所述，SubAB引起蛋白质合成的抑制。我们现在表明，蛋白质合成的抑制是短暂的，并发生作为由BiP裂解诱导的ER应激的结果;它与双链RNA激活的蛋白激酶样ER激酶（PERK）和真核起始因子-2 α（eIF 2 α）的磷酸化密切相关。PERK和eIF 2 α的磷酸化在30-60分钟达到最大，然后恢复到对照水平。用SubAB处理细胞后的蛋白质合成被抑制2小时并恢复，随后诱导应激诱导C/EBP同源蛋白（CHOP）。然而，即使在蛋白质合成恢复后，BiP降解仍在继续。SubAB处理的细胞显示细胞周期停滞在G1期，这可能是由于SubAB诱导的翻译抑制和持续延长的蛋白酶体降解引起的细胞周期蛋白D1下调。
Subtilase cytotoxin (SubAB) is a AB(5) type toxin produced by Shiga-toxigenic Escherichia coli, which exhibits cytotoxicity to Vero cells. SubAB B subunit binds to toxin receptors on the cell surface, whereas the A subunit is a subtilase-like serine protease that specifically cleaves chaperone BiP/Grp78. As noted previously, SubAB caused inhibition of protein synthesis. We now show that the inhibition of protein synthesis was transient and occurred as a result of ER stress induced by cleavage of BiP; it was closely associated with phosphorylation of double-stranded RNA-activated protein kinase-like ER kinase (PERK) and eukaryotic initiation factor-2 alpha (eIF2 alpha). The phosphorylation of PERK and eIF2 alpha was maximal at 30-60 min and then returned to the control level. Protein synthesis after treatment of cells with SubAB was suppressed for 2 h and recovered, followed by induction of stress-inducible C/EBP-homologous protein (CHOP). BiP degradation continued, however, even after protein synthesis recovered. SubAB-treated cells showed cell cycle arrest in G1 phase, which may result from cyclin D1 downregulation caused by both SubAB-induced translational inhibition and continuous prolonged proteasomal degradation.