METTL3 restricts RIPK1-dependent cell death via the ATF3-cFLIP axis in the intestinal epithelium  

作　　者：Meimei Huang Xiaodan Wang Mengxian Zhang Yuan Liu Ye‑Guang Chen 

机构地区：[1]The State Key Laboratory of Membrane Biology,Tsinghua‑Peking Center for Life Sciences,School of Life Sciences,Tsinghua University,Beijing 100084,China [2]The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors,School of Basic Medical Sciences,Jiangxi Medical College,Nanchang University,Nanchang 330031,China [3]Guangzhou National Laboratory,Guangzhou 510700,China

出　　处：《Cell Regeneration》2024年第1期238-252,共15页细胞再生(英文)

基　　金：National Natural Science Foundation of China(31988101 to YGC,92354306 to YL);National Key Research and Development Program of China(2023YFA1800603);Natural Science Foundation of Jiangxi Province(20224ACB209001);Beijing Science and Technology Plan(Z231100007223006);Shenzhen Medical Research Fund(B2302022)to YGC.

摘　　要：Intestinal epithelial cells(IECs)are pivotal for maintaining intestinal homeostasis through self-renewal,proliferation,differentiation,and regulated cell death.While apoptosis and necroptosis are recognized as distinct pathways,their intricate interplay remains elusive.In this study,we report that Mettl3-mediatedm6A modification maintains intesti-nal homeostasis by impeding epithelial cell death.Mettl3 knockout induces both apoptosis and necroptosis in IECs.Targeting different modes of cell death with specific inhibitors unveils that RIPK1 kinase activity is critical for the cell death triggered by Mettl3 knockout.Mechanistically,this occurs via them6A-mediated transcriptional regulation of Atf3,a transcription factor that directly binds to Cflar,the gene encoding the anti-cell death protein cFLIP.cFLIP inhibits RIPK1 activity,thereby suppressing downstream apoptotic and necroptotic signaling.Together,these find-ings delineate the essential role of the METTL3-ATF3-cFLIP axis in homeostatic regulation of the intestinal epithelium by blocking RIPK1 activity.

关 键 词：APOPTOSIS NECROPTOSIS Intestinal homeostasis Mettl3 m6A modification RIPK1 

分 类 号：R73[医药卫生—肿瘤]