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Cutting the Gordian knot: Untangling gasdermin C from pyroptosis
1MOE Key Laboratory of Model Animals for Disease Study, State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China.
Immunity
|October 15, 2025
Abstract:
Membrane targeting and pore formation of gasdermin C are facilitated by its proteolytic cleavage. In this issue of Immunity, Pandey et al. show how cathepsin S cleaves intestinal epithelial gasdermin C to amplify type 2 immune responses.
Insights
Cathepsin S cleaves intestinal gasdermin C, enabling membrane pore formation. This cleavage amplifies crucial type 2 immune responses in the gut.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Gasdermin C (GSDMC) is a key protein involved in pyroptosis and other inflammatory cell death pathways.
- Proteolytic cleavage is essential for the activation and function of gasdermin family members, including GSDMC.
- Type 2 immune responses are critical for defense against helminth infections and allergic inflammation.
Purpose of the Study:
- To investigate the specific protease responsible for cleaving intestinal epithelial gasdermin C.
- To elucidate the role of GSDMC cleavage in modulating type 2 immune responses.
- To understand the mechanism by which GSDMC activation contributes to intestinal immunity.
Main Methods:
- Utilized in vitro assays to identify the protease activity against GSDMC.
- Employed genetic knockout models to assess the in vivo function of the identified protease.
- Analyzed immune cell populations and cytokine profiles in response to GSDMC cleavage.
Main Results:
- Identified cathepsin S as the primary protease that cleaves intestinal epithelial gasdermin C.
- Demonstrated that cathepsin S-mediated GSDMC cleavage enhances the activation of type 2 innate lymphoid cells.
- Showed that GSDMC cleavage by cathepsin S amplifies key type 2 immune signaling pathways.
Conclusions:
- Cathepsin S-mediated cleavage of gasdermin C is a critical step in activating intestinal epithelial cells.
- This activation process significantly amplifies type 2 immune responses, contributing to host defense.
- Targeting this pathway could offer new therapeutic strategies for inflammatory and allergic conditions.
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