Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA; Department of Oral Medicine, School and Hospital of Stomatology, Shanxi Medical University, Taiyuan, Shanxi, China.
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA.
Dev Cell. 2022 Aug 22;57(16):1976-1994.e8. doi: 10.1016/j.devcel.2022.07.006. Epub 2022 Aug 1.
Gut epithelial morphogenesis is maintained by intestinal stem cells. Here, we report that depletion of N-adenosine methyltransferase subunit Mettl14 from gut epithelial cells in mice impaired colon mucosal morphogenesis, leading to increased mucosal permeability, severe inflammation, growth retardation, and premature death. Mettl14 ablation triggered apoptosis that depleted Lgr5 stem cells and disrupted colonic organoid growth and differentiation, whereas the inhibition of apoptosis rescued Mettl14-deleted mice and organoids. Mettl14 depletion disrupted N-adenomethylation on GsdmC transcripts and abolished GsdmC expression. Reconstitution of Mettl14-deleted organoids or mice with GSDMC rescued Lgr5 expression and prevented apoptosis and mouse premature death, whereas GSDMC silence eliminated LGR5 and triggered apoptosis in human colonic organoids and epithelial cells. Mechanistically, Mettl14 depletion eliminated mitochondrial GsdmC, disrupted mitochondrial membrane potential, and triggered cytochrome c release that activates the pro-apoptotic pathway. In conclusion, GsdmC N-adenomethylation protects mitochondrial homeostasis and is essential for Lgr5 cell survival to maintain normal colonic epithelial regeneration.
肠道上皮形态发生由肠干细胞维持。在这里，我们报告说，从小鼠肠道上皮细胞中耗尽 N-腺苷甲硫氨酸转移酶亚基 Mettl14 会损害结肠黏膜形态发生，导致黏膜通透性增加、严重炎症、生长迟缓以及过早死亡。Mettl14 缺失会触发细胞凋亡，耗尽 Lgr5 干细胞并破坏结肠类器官的生长和分化，而抑制细胞凋亡则可以挽救 Mettl14 缺失的小鼠和类器官。Mettl14 缺失破坏了 GsdmC 转录物上的 N-腺苷甲基化，并使 GsdmC 表达失活。用 GSDMC 重建 Mettl14 缺失的类器官或小鼠可以挽救 Lgr5 的表达并防止细胞凋亡和小鼠过早死亡，而 GSDMC 沉默消除了 LGR5 并在人结肠类器官和上皮细胞中引发细胞凋亡。在机制上，Mettl14 缺失消除了线粒体中的 GsdmC，破坏了线粒体膜电位，并引发细胞色素 c 释放，从而激活了促凋亡途径。总之，GsdmC 的 N-腺苷甲基化保护线粒体稳态，对于 Lgr5 细胞的存活以维持正常的结肠上皮再生至关重要。
