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. 2025 Oct 14;58(10):2439-2455.e8.
doi: 10.1016/j.immuni.2025.06.018. Epub 2025 Jul 22.

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

Surya P Pandey  1 , Donghui Yang  2 , Lee Hedden  1 , Colin R Laughlin  1 , Weihong Wang  3 , Ariadna S Soto  1 , Halah Winner  4 , Luzmariel Medina Sanchez  4 , Edith E Campana  4 , Clarisse Engl  1 , Yanlin Zeng  5 , Mohit Rana  1 , Lauren Van Der Kraak  1 , Mackenzie J Bender  1 , Joshua Prokopec  3 , Julia M Ferrick  6 , Xinan Meng  7 , Erica Fong  8 , Mai Sun  8 , Steven J Mullett  9 , Matthew MacDonald  10 , Stacy L Gelhaus  9 , Simon C Watkins  11 , Marlies Meisel  12 , Jakob von Moltke  13 , Suhong Xu  7 , Yi-Nan Gong  14 , Reinhard Hinterleitner  15
Affiliations

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

Surya P Pandey et al. Immunity. .

Abstract

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.

Keywords: Cathepsin S; Gasdermin C; Rab7; helminth; intestinal epithelial cells; protist; type 2 immune.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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