Calpain Activation by the Shigella flexneri Effector VirA Regulates Key Steps in the Formation and Life of the Bacterium's Epithelial Niche
Calpain Activation by the Shigella flexneri Effector VirA Regulates Key Steps in the Formation and Life of the Bacterium's Epithelial Niche
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DOI：
10.1016/j.chom.2012.01.013
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发表时间：
2012-03-15
影响因子：
30.3
通讯作者：
Arbibe, Laurence
中科院分区：
文献类型：
--
作者：
Bergounioux, Jean;Elisee, Ruben;Arbibe, Laurence
肠道病原体福氏志贺氏菌侵入上皮细胞，导致炎症和组织破坏。我们报告说，志贺氏菌感染的上皮细胞诱导早期的遗传毒性压力，但由此产生的p53反应和细胞死亡受损，由于细菌的能力，促进p53降解，主要是通过钙蛋白酶蛋白酶激活。钙蛋白酶激活由志贺氏菌毒力效应子VirA促进，并依赖于钙通量和内源性钙蛋白酶抑制剂钙蛋白酶抑制素的消耗。此外，尽管VirA诱导的钙蛋白酶活性对于调节驱动细菌摄取的细胞骨架事件至关重要，但钙蛋白酶活化最终导致坏死细胞死亡，从而限制志贺氏菌胞内生长。因此，钙蛋白酶通过在感染早期破坏p53依赖的DNA修复反应并调节志贺氏菌上皮复制小生境的形成和最终死亡，在多个步骤中调节志贺氏菌的发病机制。
The enteropathogen Shigella flexneri invades epithelial cells, leading to inflammation and tissue destruction. We report that Shigella infection of epithelial cells induces an early genotoxic stress, but the resulting p53 response and cell death are impaired due to the bacterium's ability to promote p53 degradation, mainly through calpain protease activation. Calpain activation is promoted by the Shigella virulence effector VirA and dependent on calcium flux and the depletion of the endogenous calpain inhibitor calpastatin. Further, although VirA-induced calpain activity is critical for regulating cytoskeletal events driving bacterial uptake, calpain activation ultimately leads to necrotic cell death, thereby restricting Shigella intracellular growth. Therefore, calpains work at multiple steps in regulating Shigella pathogenesis by disrupting the p53-dependent DNA repair response early during infection and regulating both formation and ultimate death of the Shigella epithelial replicative niche.