Gasdermin C cleavage by Cathepsin S modulates Rab7 vesicles in intestinal epithelial cells to amplify anti-helminth...

Gasdermins are canonically associated with plasma membrane pore formation and lytic cell death. Gasdermin C (GsdmC), predominantly expressed in intestinal epithelial cells (IECs), seems to operate independently of these canonical roles. Here, we show that activated GsdmC is increased in response to type 2 immunity in the gut, driven by Cathepsin S (CTSS)-mediated cleavage. Although IEC cell death is not the main consequence of GsdmC cleavage, inserting a single amino acid (aa) within the lipid-binding motif to match that of the other gasdermins enhanced GsdmC oligomerization and increased GsdmC-mediated cell death. Mechanistically, instead of localizing to the plasma membrane, we showed that cleaved GsdmC targeted Rab7⁺ vesicles, such as late endosomes. This modulated lipid droplet accumulation, which promoted goblet cell hyperplasia and type 2 immune responses. These findings demonstrate how GsdmC in IEC protects against helminth infection and expands the role of gasdermins beyond cell death and cytokine release.