Caspase-5c amplifies Wnt signaling to sustain intestinal renewal

A Nature study identifies CASP5C, a human intestinal epithelial isoform of caspase-5, as a catalytic amplifier of Wnt signaling. CASP5C binds Dishevelled and cleaves APC at Asp556, destabilizing the β-catenin destruction complex and boosting Wnt activity to promote transit-amplifying cell proliferation and organoid growth; CASP5A and CASP5B lack this activity. CASP5C is upregulated during injury and in inflammatory bowel disease, revealing a non-immune role for inflammatory caspases in intestinal homeostasis.