Clostridium difficile toxin B activates calcium influx required for actin disassembly during cytotoxicity.
Clostridium difficile toxin B activates calcium influx required for actin disassembly during cytotoxicity.
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艰难梭菌毒素 B 会激活细胞毒性过程中肌动蛋白分解所需的钙流入。
DOI：
10.1152/ajpgi.1995.268.3.g487
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
Yakubovich,M
中科院分区：
文献类型：
--
作者：
Gilbert,RJ;Pothoulakis,C;LaMont,JT;Yakubovich,M
艰难梭菌毒素 B（一种与抗生素相关结肠炎相关的蛋白质毒素）的主要细胞反应是肌动蛋白微丝的分解。尽管已提出受体激活的信号转导机制来介导这些作用，但肌动蛋白分解之前的细胞内事件尚不清楚。在 NIH-3T3 成纤维细胞中，毒素 B 诱导细胞内钙升高，其上升时间要么慢（几分钟），要么快（秒），然后钙浓度持续升高。毒素 B 后稳态钙分布的亚细胞分析表明，钙的增加在整个细胞质中是均匀的，并且不会根据初始钙增加的动力学而变化。所有钙反应均被无钙缓冲液或含有氯化镧的缓冲液替代而阻断，表明钙的增加可归因于钙从细胞外空间流入。在原代培养的胃平滑肌和 AR42J 胰腺肿瘤细胞中观察到定量相似的反应，表明毒素诱导的钙信号转导在细胞类型之间是保守的。对毒素 B 的形态学反应包括肌动蛋白细胞骨架与膜附着物的连续解离、肌动蛋白应力纤维从外围到核周区域的回缩、纤维排列的丧失和细胞变圆。与毒素 B 相关的肌动蛋白重组可通过在无钙培养基中孵育细胞或用可渗透细胞的钙螯合剂夹住细胞内钙来阻断。这些结果表明，艰难梭菌毒素 B 激活的钙内流是与细胞毒性相关的丝状肌动蛋白分解的必要条件。
The principal cellular response to Clostridium difficile toxin B, a protein toxin associated with antibiotic-associated colitis, is the disassembly of actin microfilaments. Although receptor-activated signal transduction mechanisms have been proposed to mediate these effects, the intracellular events that precede actin breakdown are unknown. In NIH-3T3 fibroblasts, toxin B induced an elevation of intracellular calcium possessing either a slow (minutes) or fast (seconds) rise time, followed by a sustained elevation of calcium concentration. Subcellular analysis of steady-state calcium distribution after toxin B demonstrated that the increase of calcium was homogeneous throughout the cytosol and did not vary based on the kinetics of the initial calcium rise. All calcium responses were blocked by substitution with calcium-free buffer or buffer containing lanthanum chloride, indicating that the rise in calcium was attributable to calcium influx from the extracellular space. Quantitatively similar responses were observed in primary cultured gastric smooth muscle and AR42J pancreatic tumor cells, suggesting that toxin-induced calcium signal transduction was conserved between cell types. The morphological response to toxin B consisted of sequential dissociation of the actin cytoskeleton from membrane attachments, retraction of actin stress fibers from the periphery to the perinuclear region, loss of fibre alignment, and cell rounding. The actin reorganization associated with toxin B was blocked by incubation of cells in calcium-free media or the clamping of intracellular calcium with cell-permeant calcium chelating agents. These results demonstrate that the calcium influx activated by C. difficile toxin B is a necessary condition for the breakdown of filamentous actin associated with cytotoxicity.
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