Dysregulated hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing.

Abstract

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.

• Authors: Shouwen Chen, Dahai Yang, Ying Wen, Zhiwei Jiang, Lingzhi Zhang, Jiatiao Jiang, Yaozhen Chen, Tianjian Hu, Qiyao Wang, Yuanxing Zhang, Qin Liu
• Journal: PLoS pathogens (PLoS Pathog) Vol. 14 Issue 8 Pg. e1007240 (08 2018) ISSN: 1553-7374 [Electronic] United States
• PMID: 30138458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Outer Membrane Proteins
• Hemolysin Proteins
• Inflammasomes
• Lipopolysaccharides
• CASP4 protein, human
• Caspases
• Caspases, Initiator

Topics

• Animals
• Bacterial Outer Membrane Proteins (metabolism)
• Caco-2 Cells
• Caspases (genetics, metabolism)
• Caspases, Initiator (genetics, metabolism)
• Cytosol (metabolism)
• Extracellular Vesicles (metabolism)
• Gram-Negative Bacteria (immunology, metabolism, ultrastructure)
• HEK293 Cells
• HT29 Cells
• HeLa Cells
• Hemolysin Proteins (genetics, metabolism)
• Humans
• Immunity, Innate (genetics)
• Inflammasomes (metabolism)
• Inflammation (immunology, metabolism)
• Lipopolysaccharides (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Transfection
• Up-Regulation (genetics)