期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2101189118
关键词
gasdermin; Yersinia; RIPK1; neutrophils; caspases
资金
- European Research Council [ERC2017-CoG-770988-InflamCellDeath]
- Swiss National Science Foundation [310030_175576, 310030B_198005, 310030_184751]
- National University of Singapore
- Ministry of Education
- Mark Foundation [19-011MIA]
- NIH [R01-139102]
- Swiss National Science Foundation (SNF) [310030B_198005, 310030_175576, 310030_184751] Funding Source: Swiss National Science Foundation (SNF)
Injection of effector proteins by pathogenic organisms to block host innate immune signaling is a common strategy for establishing infection. This study reveals that GSDME is activated in a RIPK1-dependent manner and promotes neutrophil pyroptosis and IL-113 release critical for anti-Yersinia defense, establishing it as an important mediator to counteract pathogen blockade of innate immune signaling.
Injection of effector proteins to block host innate immune signaling is a common strategy used by many pathogenic organisms to establish an infection. For example, pathogenic Yersinia species inject the acetyltransferase YopJ into target cells to inhibit NF-xB and MAPK signaling. To counteract this, detection of YopJ activity in myeloid cells promotes the assembly of a RIPK1-caspase-8 death- inducing platform that confers antibacterial defense. While recent studies revealed that caspase-8 cleaves the pore-forming protein gasdermin D to trigger pyroptosis in macrophages, whether RIPK1 activates additional substrates downstream of caspase-8 to promote host defense is unclear. Here, we report that the related gasdermin family member gasdermin E (GSDME) is activated upon detection of YopJ activity in a RIPK1 kinase-dependent manner. Specifically, GSDME promotes neutrophil pyroptosis and IL-113 release, which is critical for anti-Yersinia defense. During in vivo infection, IL-113 neutralization increases bacterial burden in wild-type but not Gsdmedeficient mice. Thus, our study establishes GSDME as an important mediator that counteracts pathogen blockade of innate immune signaling.
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