Dysregulated hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing.
Dysregulated hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing.
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溶血素失调释放细菌外膜囊泡用于胞质脂多糖传感
DOI：
10.1371/journal.ppat.1007240
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发表时间：
2018-08
期刊：
影响因子：
6.7
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Chen S;Yang D;Wen Y;Jiang Z;Zhang L;Jiang J;Chen Y;Hu T;Wang Q;Zhang Y;Liu Q
炎症性 caspase-11/4/5 识别入侵革兰氏阴性菌的胞质 LPS，诱导细胞焦亡和细胞因子释放，形成快速的先天抗菌防御。由于细胞外或液泡限制的细菌被认为很少进入细胞质，因此它们的 LPS 如何暴露于胞质传感器是病原体识别的关键事件。溶血素是一种形成孔的细菌毒素，通常认为它会破裂细胞膜，导致细胞裂解。溶血素是否以及如何参与非典型炎症小体信号传导仍未被发现。在这里，我们发现溶血素过表达的肠杆菌引发人肠上皮细胞系中 caspase-4 的激活显着增加。溶血素通过动力依赖的内吞作用促进胞外细菌的 LPS 胞质递送。此外，我们发现溶血素很大程度上与细菌外膜囊泡（OMV）相关，并诱导含有 OMV 的液泡破裂，随后增加了 LPS 与细胞溶质传感器的接触。因此，溶血素的过度表达促进了小鼠体内 caspase-11 依赖性 IL-18 的分泌和肠道炎症，这与限制体内细菌定植有关。总之，我们的工作揭示了一个概念，即溶血素通过释放用于胞质 LPS 传感的 OMV 来促进非典型炎症小体激活，这为了解肠道抗菌防御中通过 caspase-11/4 对溶血素失调的先天免疫监视提供了见解。
Inflammatory caspase-11/4/5 recognize cytosolic LPS from invading Gram-negative bacteria and induce pyroptosis and cytokine release, forming rapid innate antibacterial defenses. Since extracellular or vacuole-constrained bacteria are thought to rarely access the cytoplasm, how their LPS are exposed to the cytosolic sensors is a critical event for pathogen recognition. Hemolysin is a pore-forming bacterial toxin, which was generally accepted to rupture cell membrane, leading to cell lysis. Whether and how hemolysin participates in non-canonical inflammasome signaling remains undiscovered. Here, we show that hemolysin-overexpressed enterobacteria triggered significantly increased caspase-4 activation in human intestinal epithelial cell lines. Hemolysin promoted LPS cytosolic delivery from extracellular bacteria through dynamin-dependent endocytosis. Further, we revealed that hemolysin was largely associated with bacterial outer membrane vesicles (OMVs) and induced rupture of OMV-containing vacuoles, subsequently increasing LPS exposure to the cytosolic sensor. Accordingly, overexpression of hemolysin promoted caspase-11 dependent IL-18 secretion and gut inflammation in mice, which was associated with restricting bacterial colonization in vivo. Together, our work reveals a concept that hemolysin promotes noncanonical inflammasome activation via liberating OMVs for cytosolic LPS sensing, which offers insights into innate immune surveillance of dysregulated hemolysin via caspase-11/4 in intestinal antibacterial defenses.
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影响因子：
6.4
作者：
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作者：
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6.7
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