美国康奈尔大学J. Magarian Blander团队的研究显示，半胱氨酸天冬氨酸蛋白酶5c通过APC切割放大Wnt，促进肠道稳态。相关论文于2026年4月22日发表在《自然》杂志上。

在这里，该研究团队发现CASP5仅限于人类肠上皮，并表现为三种亚型——casp5a、CASP5B和CASP5C，其中CASP5C独特地促进Wnt信号传导，这对于上皮的发育和再生至关重要。该研究组发现，在结肠上皮细胞中，连接Wnt受体和β-连环蛋白破坏复合物的Disheveled是CASP5的一个重要结合伙伴。Disheveled通过其DEP （disheveled， EGL-10和pleckstrin）结构域与CASP5催化结构域相互作用。CASP5C缺乏CASP5A和CASP5B的抑制性caspase激活和募集结构域（CARD），在Armadillo重复结构域Asp556处切割中心支架蛋白APC，破坏β-catenin破坏复合物的稳定，从而增强Wnt信号传导。CASP5C在肠干细胞依赖Wnt的子代转运扩增细胞中表达高峰，而CASP5A和CASP5B在成熟肠细胞中占主导地位。内源性和异位CASP5C驱动结肠和小肠类器官的生长，已知这需要转运扩增细胞的增殖。

此外，CASP5C可选择性诱导肠上皮损伤，在炎症性肠病中表达增加。其中，CASP5C是Wnt信号的酶促放大器，在Wnt梯度下降的情况下，切割APC以维持转运扩增细胞的增殖，从而保护上皮的更新。这些发现拓宽了炎性半胱天冬酶在先天免疫之外的作用，揭示了它们对组织稳态的贡献。

研究人员表示，Caspase 5 （CASP5）是炎性半胱氨酸蛋白酶Caspase家族的一员，参与炎症和细胞死亡。CASP5与炎性CASP4具有最高的同源性，但CASP4对于非典型炎性体激活至关重要，CASP5是可有可无的，其功能尚不清楚。

附：英文原文

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

Author: Jia, Baosen, Shi, Yuhua, Hong, Yourae, Yang, Chongbo, Roycroft, Dylan, Kamal, Shahida, Mukherjee, Sushmita, Ueberheide, Beatrix, Grier, Alex, Witherspoon, Mavee, Bilal, Maneeza, He, Bing, Lacko, Lauretta A., Lipkin, Steven M., Tejpar, Sabine, Blander, J. Magarian

Issue&Volume: 2026-04-22

Abstract: Caspase 5 (CASP5) is a member of the inflammatory caspase family of cysteine proteases that is involved in inflammation and cell death1,2,3. CASP5 shares the highest homology with inflammatory CASP4, but whereas CASP4 is essential for noncanonical inflammasome activation, CASP5 is dispensable4,5,6, 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.

DOI: 10.1038/s41586-026-10343-8

Source: https://www.nature.com/articles/s41586-026-10343-8