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Gasdermin C links nutrient and immune signaling to protist-induced type 2 immunity and intestinal repair

Keller, A.; Adeniyi, A.; Akkaya-Colak, K. B.; Festing, M. H.; Schwieters, A.; Kumar, R.; Sledziona, J.; Gupta, K.; Stevens, P.; Pietrzak, M.; Coppola, V.; Ranganathan, P.; Ahmer, B.; Forero, A.; Knoblaugh, S. E.; Mihaylova, M. M.

2025-09-27 physiology
10.1101/2025.09.24.678435 bioRxiv
Show abstract

The Gasdermin family of proteins has recently been implicated in tissue repair and homeostasis through their effector function in type 2 immunity and pyroptosis. Yet the role of Gasdermin C proteins has not been fully characterized in the mammalian intestine, where environmental factors can influence epithelial regeneration and repair. Here we report that Gsdmc2-4 genes are regulated in a nutrient-dependent manner and are suppressed with aging. We uncover that commensal protists in the gut regulate Gsdmc2-4 expression through activation of type 2 immune responses. In intestinal organoid experiments, we find that STAT6 is necessary for Gsdmc2-4 induction in response to type 2 cytokines; however, basal expression of Gsdmc2-4 in vivo is only partially diminished in Stat6 knockout animals. Finally, in protist-colonized animals, loss of Gsdmc1-4 exacerbated mucosal erosion and inflammation in response to Dextran sodium sulfate (DSS) exposure, implicating these proteins in coordinating epithelial responses to injury.

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