2. Academic Validation
  3. Caspase 5c amplifies Wnt via APC cleavage to promote intestinal homeostasis

Caspase 5c amplifies Wnt via APC cleavage to promote intestinal homeostasis

  • Nature. 2026 Apr;652(8112):1362-1374. doi: 10.1038/s41586-026-10343-8.
Baosen Jia # 1 2,  Yuhua Shi # 1 2,  Yourae Hong 3 4,  Chongbo Yang 1 2,  Dylan Roycroft 1 2,  Shahida Kamal 1 2,  Sushmita Mukherjee 5,  Beatrix Ueberheide 6,  Alex Grier 1 2,  JRI Live Cell Bank,  Mavee Witherspoon 2,  Maneeza Bilal 7,  Bing He 7,  Lauretta A Lacko 2,  Steven M Lipkin 1 2 8,  Sabine Tejpar 3 9,  J Magarian Blander 10 11 12 13 14
Affiliations

Affiliations

  • 1 Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 2 Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 3 Digestive Oncology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium.
  • 4 Cancer Research UK Scotland Institute, Glasgow, UK.
  • 5 Department of Biochemistry, Microscopy and Image Analysis Core Facility, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 6 Office of Collaborative Science, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.
  • 7 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 8 Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 9 Universitair Ziekenhuis Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium.
  • 10 Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA. [email protected].
  • 11 Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. [email protected].
  • 12 Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA. [email protected].
  • 13 Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA. [email protected].
  • 14 Immunology and Microbial Pathogenesis Program, Weill Cornell and Sloan Kettering Institute Graduate School of Medical Sciences, New York, NY, USA. [email protected].
  • # Contributed equally.
PMID: 42020739 DOI: 10.1038/s41586-026-10343-8
Abstract

Caspase 5 (CASP5) is a member of the inflammatory Caspase family of cysteine proteases that is involved in inflammation and cell death1-3. CASP5 shares the highest homology with inflammatory CASP4, but whereas CASP4 is essential for noncanonical inflammasome activation, CASP5 is dispensable4-6, and its function remains unknown. Here we show that CASP5 is restricted to the human intestinal epithelium and manifests as three isoforms-CASP5A, CASP5B and CASP5C-among which CASP5C uniquely promotes Wnt signalling, which is essential for epithelial development and regeneration7. We identified dishevelled, which bridges Wnt receptors to the β-catenin destruction complex8, as a prominent CASP5 binding partner in colonic epithelial cells. Dishevelled interacts with the CASP5 catalytic domain through its DEP (dishevelled, EGL-10 and pleckstrin) domain. Lacking the inhibitory Caspase activation and recruitment domain (CARD) of CASP5A and CASP5B, CASP5C cleaves the central scaffold protein APC at Asp556 in the Armadillo repeat domain, destabilizing the β-catenin destruction complex and thereby enhancing Wnt signalling. CASP5C expression peaks in transit-amplifying cells, the Wnt-reliant progeny of intestinal stem cells7, whereas CASP5A and CASP5B predominate in mature enterocytes. Endogenous and ectopic CASP5C drive growth of colonic and small intestinal organoids, which is known to require proliferation of transit-amplifying cells9. Furthermore, CASP5C is selectively induced upon intestinal epithelial injury, and its expression is increased in inflammatory bowel disease. Thus, CASP5C is an enzymatic amplifier of Wnt signalling that cleaves APC to sustain proliferation of transit-amplifying cells amid a declining Wnt gradient, safeguarding epithelial renewal. These findings broaden the roles of inflammatory caspases beyond innate immunity, uncovering their contribution to tissue homeostasis.

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