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

Surya P. Pandey; Donghui Yang; Lee Hedden; Colin R. Laughlin; Weihong Wang; Ariadna S. Soto; Halah Winner; Luzmariel Medina Sanchez; Edith E. Campana; Clarisse Engl; Yanlin Zeng; Mohit Rana; Lauren Van Der Kraak; Mackenzie J. Bender; Joshua Prokopec; Julia M. Ferrick; Xinan Meng; Erica Fong; Mai Sun; Steven J. Mullett; Matthew MacDonald; Stacy L. Gelhaus; Simon C. Watkins; Marlies Meisel; Jakob von Moltke; Suhong Xu; Yi Nan Gong; Reinhard Hinterleitner

doi:10.1016/j.immuni.2025.06.018

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

Surya P. Pandey, Donghui Yang, Lee Hedden, Colin R. Laughlin, Weihong Wang, Ariadna S. Soto, Halah Winner, Luzmariel Medina Sanchez, Edith E. Campana, Clarisse Engl, Yanlin Zeng, Mohit Rana, Lauren Van Der Kraak, Mackenzie J. Bender, Joshua Prokopec, Julia M. Ferrick, Xinan Meng, Erica Fong, Mai Sun, Steven J. MullettMatthew MacDonald, Stacy L. Gelhaus, Simon C. Watkins, Marlies Meisel, Jakob von Moltke, Suhong Xu, Yi Nan Gong, Reinhard Hinterleitner

Houston Methodist

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2439-2455.e8
Journal	Immunity
Volume	58
Issue number	10
DOIs	https://doi.org/10.1016/j.immuni.2025.06.018
State	Published - Oct 14 2025

Keywords

Cathepsin S
Gasdermin C
Rab7
helminth
intestinal epithelial cells
protist
type 2 immune

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2025.06.018

Cite this

Pandey, S. P., Yang, D., Hedden, L., Laughlin, C. R., Wang, W., Soto, A. S., Winner, H., Medina Sanchez, L., Campana, E. E., Engl, C., Zeng, Y., Rana, M., Van Der Kraak, L., Bender, M. J., Prokopec, J., Ferrick, J. M., Meng, X., Fong, E., Sun, M., ... Hinterleitner, R. (2025). Gasdermin C cleavage by Cathepsin S modulates Rab7 vesicles in intestinal epithelial cells to amplify anti-helminth immunity. Immunity, 58(10), 2439-2455.e8. https://doi.org/10.1016/j.immuni.2025.06.018

Pandey, SP, Yang, D, Hedden, L, Laughlin, CR, Wang, W, Soto, AS, Winner, H, Medina Sanchez, L, Campana, EE, Engl, C, Zeng, Y, Rana, M, Van Der Kraak, L, Bender, MJ, Prokopec, J, Ferrick, JM, Meng, X, Fong, E, Sun, M, Mullett, SJ, MacDonald, M, Gelhaus, SL, Watkins, SC, Meisel, M, von Moltke, J, Xu, S, Gong, YN & Hinterleitner, R 2025, 'Gasdermin C cleavage by Cathepsin S modulates Rab7 vesicles in intestinal epithelial cells to amplify anti-helminth immunity', Immunity, vol. 58, no. 10, pp. 2439-2455.e8. https://doi.org/10.1016/j.immuni.2025.06.018

@article{16055078236a4109bf16b5a9668c6a77,

title = "Gasdermin C cleavage by Cathepsin S modulates Rab7 vesicles in intestinal epithelial cells to amplify anti-helminth 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",

author = "Pandey, \{Surya P.\} and Donghui Yang and Lee Hedden and Laughlin, \{Colin R.\} and Weihong Wang and Soto, \{Ariadna S.\} and Halah Winner and \{Medina Sanchez\}, Luzmariel and Campana, \{Edith E.\} and Clarisse Engl and Yanlin Zeng and Mohit Rana and \{Van Der Kraak\}, Lauren and Bender, \{Mackenzie J.\} and Joshua Prokopec and Ferrick, \{Julia M.\} and Xinan Meng and Erica Fong and Mai Sun and Mullett, \{Steven J.\} and Matthew MacDonald and Gelhaus, \{Stacy L.\} and Watkins, \{Simon C.\} and Marlies Meisel and \{von Moltke\}, Jakob and Suhong Xu and Gong, \{Yi Nan\} and Reinhard Hinterleitner",

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Inc.",

year = "2025",

month = oct,

day = "14",

doi = "10.1016/j.immuni.2025.06.018",

language = "English (US)",

volume = "58",

pages = "2439--2455.e8",

journal = "Immunity",

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T1 - Gasdermin C cleavage by Cathepsin S modulates Rab7 vesicles in intestinal epithelial cells to amplify anti-helminth immunity

AU - Pandey, Surya P.

AU - Yang, Donghui

AU - Hedden, Lee

AU - Laughlin, Colin R.

AU - Wang, Weihong

AU - Soto, Ariadna S.

AU - Winner, Halah

AU - Medina Sanchez, Luzmariel

AU - Campana, Edith E.

AU - Engl, Clarisse

AU - Zeng, Yanlin

AU - Rana, Mohit

AU - Van Der Kraak, Lauren

AU - Bender, Mackenzie J.

AU - Prokopec, Joshua

AU - Ferrick, Julia M.

AU - Meng, Xinan

AU - Fong, Erica

AU - Sun, Mai

AU - Mullett, Steven J.

AU - MacDonald, Matthew

AU - Gelhaus, Stacy L.

AU - Watkins, Simon C.

AU - Meisel, Marlies

AU - von Moltke, Jakob

AU - Xu, Suhong

AU - Gong, Yi Nan

AU - Hinterleitner, Reinhard

PY - 2025/10/14

Y1 - 2025/10/14

N2 - 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.

AB - 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.

KW - Cathepsin S

KW - Gasdermin C

KW - Rab7

KW - helminth

KW - intestinal epithelial cells

KW - protist

KW - type 2 immune

UR - https://www.scopus.com/pages/publications/105011295381

UR - https://www.scopus.com/inward/citedby.url?scp=105011295381&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2025.06.018

DO - 10.1016/j.immuni.2025.06.018

M3 - Article

C2 - 40701157

AN - SCOPUS:105011295381

SN - 1074-7613

VL - 58

SP - 2439-2455.e8

JO - Immunity

JF - Immunity

IS - 10

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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