2. Academic Validation
  3. Gasdermin C cleavage by Cathepsin S modulates Rab7 vesicles in intestinal epithelial cells to amplify anti-helminth immunity

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

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: yngong@pitt.edu.
  • 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: reinhard@pitt.edu.
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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