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PMID:23684308

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Citation

Kobayashi, T, Ogawa, M, Sanada, T, Mimuro, H, Kim, M, Ashida, H, Akakura, R, Yoshida, M, Kawalec, M, Reichhart, JM, Mizushima, T and Sasakawa, C (2013) The Shigella OspC3 effector inhibits caspase-4, antagonizes inflammatory cell death, and promotes epithelial infection. Cell Host Microbe 13:570-83

Abstract

Caspase-mediated inflammatory cell death acts as an intrinsic defense mechanism against infection. Bacterial pathogens deploy countermeasures against inflammatory cell death, but the mechanisms by which they do this remain largely unclear. In a screen for Shigella flexneri effectors that regulate cell death during infection, we discovered that Shigella infection induced acute inflammatory, caspase-4-dependent epithelial cell death, which is counteracted by the bacterial OspC3 effector. OspC3 interacts with the caspase-4-p19 subunit and inhibits its activation by preventing caspase-4-p19 and caspase-4-p10 heterodimerization by depositing the conserved OspC3 X1-Y-X₂-D-X₃ motif at the putative catalytic pocket of caspase-4. Infection of guinea pigs with a Shigella ospC3-deficient mutant resulted in enhanced inflammatory cell death and associated symptoms, correlating with decreased bacterial burdens. Salmonella Typhimurium and enteropathogenic Escherichia coli infection also induced caspase-4-dependent epithelial death. These findings highlight the importance of caspase-4-dependent innate immune responses and demonstrate that Shigella delivers a caspase-4-specific inhibitor to delay epithelial cell death and promote infection.

Links

PubMed Online version:10.1016/j.chom.2013.04.012

Keywords

Animals; Bacterial Proteins/genetics; Bacterial Proteins/metabolism; Caspases, Initiator/metabolism; Cell Death; Cell Line; DNA, Bacterial/chemistry; DNA, Bacterial/genetics; Disease Models, Animal; Dysentery, Bacillary/immunology; Dysentery, Bacillary/microbiology; Dysentery, Bacillary/pathology; Enzyme Inhibitors/metabolism; Epithelial Cells/microbiology; Escherichia coli/immunology; Escherichia coli/pathogenicity; Gene Knockout Techniques; Guinea Pigs; Host-Pathogen Interactions; Humans; Molecular Sequence Data; Protein Binding; Protein Interaction Mapping; Salmonella typhimurium/immunology; Salmonella typhimurium/pathogenicity; Sequence Analysis, DNA; Shigella flexneri/genetics; Shigella flexneri/immunology; Shigella flexneri/pathogenicity; Virulence Factors/genetics; Virulence Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

SHIFL:Q99QF4

GO:0034054: negative regulation by symbiont of host defense-related programmed cell death

ECO:0000315:

P

Organism: Shigella Flexneri protein: OspC3 Supplementary figure 1A shows that "...one of the mutants lacking ospC3 (ΔospC3) greatly enhanced cell death at 2 and 4 hr compared to the other effector mutants and YSH6000 (wild-type [WT] Shigella) (Figure S1A), suggesting that OspC3 suppresses the cell death response to Shigella infection." Host: human skin cells

complete
CACAO 12993

Notes

See also

References

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