Sir William Dunn School of Pathology, University of Oxford, Oxfordshire, UK.
Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
EMBO Rep. 2020 Dec 3;21(12):e48892. doi: 10.15252/embr.201948892. Epub 2020 Nov 1.
Caspase malfunction in stem cells often precedes the appearance and progression of multiple types of cancer, including human colorectal cancer. However, the caspase-dependent regulation of intestinal stem cell properties remains poorly understood. Here, we demonstrate that Dronc, the Drosophila ortholog of caspase-9/2 in mammals, limits the number of intestinal progenitor cells and their entry into the enterocyte differentiation programme. Strikingly, these unexpected roles for Dronc are non-apoptotic and have been uncovered under experimental conditions without epithelial replenishment. Supporting the non-apoptotic nature of these functions, we show that they require the enzymatic activity of Dronc, but are largely independent of the apoptotic pathway. Alternatively, our genetic and functional data suggest that they are linked to the caspase-mediated regulation of Notch signalling. Our findings provide novel insights into the non-apoptotic, caspase-dependent modulation of stem cell properties that could improve our understanding of the origin of intestinal malignancies.
细胞凋亡蛋白酶在干细胞中的功能障碍常常先于多种类型癌症的出现和发展，包括人类结直肠癌。然而，细胞凋亡蛋白酶对肠道干细胞特性的调控仍知之甚少。在这里，我们证明果蝇 caspase-9/2 的同源物 Dronc 限制了肠祖细胞的数量及其进入肠细胞分化程序。引人注目的是，这些对 Dronc 的意想不到的作用是非凋亡性的，并且在没有上皮细胞补充的实验条件下被揭示出来。支持这些功能的非凋亡性质，我们表明它们需要 Dronc 的酶活性，但在很大程度上独立于凋亡途径。或者，我们的遗传和功能数据表明，它们与 caspase 介导的 Notch 信号转导调节有关。我们的研究结果为非凋亡性、依赖细胞凋亡蛋白酶的干细胞特性调节提供了新的见解，这可能有助于我们理解肠道恶性肿瘤的起源。
