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

  • Immunity. 2025 Jul 16:S1074-7613(25)00287-0. doi: 10.1016/j.immuni.2025.06.018.
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
  • 1. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 2. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA; School of Medicine, Tsinghua University, Beijing, China.
  • 3. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
  • 4. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 5. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; School of Medicine, Tsinghua University, Beijing, China.
  • 6. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA; Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 7. International Biomedicine-X Research Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, and the Zhejiang University, University of Edinburgh Institute, Haining 314400, Zhejiang, China.
  • 8. Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA.
  • 9. Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 10. Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 11. Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 12. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
  • 13. Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
  • 14. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 15. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
PMID: 40701157 DOI: 10.1016/j.immuni.2025.06.018
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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