文献类型：期刊文献

英文题名：Dysregulated hemolysin liberates bacteria outer membrane vesicles for cytosolic lipopolysaccharide sensing

作者：Chen, Shouwen[1];Yang, Dahai[1,2];Wen, Ying[1];Jiang, Zhiwei[1];Zhang, Lingzhi[1,3,4];Jiang, Jiatiao[1];Chen, Yaozhen[5];Hu, Tianjian[1];Wang, Qiyao[1,2];Zhang, Yuanxing[1,2];Liu, Qin[1,2,6]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[2]Shanghai Engn Res Ctr Maricultured Anim Vaccines, Shanghai, Peoples R China;[3]Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA;[4]Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA;[5]Xijing Hosp, Dept Transfus Med, Xian, Shaanxi, Peoples R China;[6]Qingdao Natl Lab Marine Sci & Technol, Lab Marine Biol & Biotechnol, Qingdao, Peoples R China

年份：2018

卷号：14

期号：8

外文期刊名：PLOS PATHOGENS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000443296800034)】；

基金：This work was supported by the National Natural Science Foundation of China No. 31622059 (QL) and 31430090 (YZ) and the Fundamental Research Funds for the Central Universities No. 222201717019 and 222201718004. DY was supported by the Young Elite Scientists Sponsorship Program by CAST No. 2016QNRC001, Shanghai Chenguang Program No.16CG33 and Talent Program of School of Biotechnology in East China University of Science and Technology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

语种：英文

摘要：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.