RIPK1 activates distinct gasdermins in macrophages and neutrophils upon 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.

Automated summary

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.