The Shigella OspC3 Effector Inhibits Caspase-4, Antagonizes Inflammatory Cell Death, and Promotes Epithelial Infection

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• 作者：Taira Kobayashi¹ ; ² ; Michinaga Ogawa¹ ; Takahito Sanada¹ ; ² ; Hitomi Mimuro² ; Minsoo Kim¹ ; ³ ; Hiroshi Ashida¹ ; ³ ; Reiko Akakura¹ ; Mitsutaka Yoshida⁴ ; Magdalena Kawalec⁵ ; Jean-Marc Reichhart⁵ ; Tsunehiro Mizushima⁶ ; Chihiro Sasakawa¹ ; ³ ; ⁷ ; ⁸ ; ^{sasakawa@ims.u-tokyo.ac.jp}
• 刊名：Cell Host Microbe
• 出版年：2013
• 出版时间：15 May, 2013
• 年：2013
• 卷：13
• 期：5
• 页码：570-583
• 全文大小：5430 K

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Summary

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.