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

IF 4 Q2 CELL & TISSUE ENGINEERING
Meimei Huang, Xiaodan Wang, Mengxian Zhang, Yuan Liu, Ye-Guang Chen
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引用次数: 0

Abstract

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-mediated m6A modification maintains intestinal 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 the m6A-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 findings delineate the essential role of the METTL3-ATF3-cFLIP axis in homeostatic regulation of the intestinal epithelium by blocking RIPK1 activity.

METTL3 在肠上皮细胞中通过 ATF3-cFLIP 轴限制 RIPK1 依赖性细胞死亡。
肠上皮细胞(IECs)是通过自我更新、增殖、分化和调节细胞死亡来维持肠道平衡的关键。虽然凋亡和坏死被认为是不同的途径,但它们之间错综复杂的相互作用仍然难以捉摸。在这项研究中,我们报告了 Mettl3 介导的 m6A 修饰通过阻碍上皮细胞死亡来维持肠道稳态。Mettl3 基因敲除可诱导 IECs 细胞凋亡和坏死。用特异性抑制剂针对不同的细胞死亡模式发现,RIPK1激酶活性对Mettl3基因敲除引发的细胞死亡至关重要。从机制上讲,这是通过 m6A 介导的 Atf3 转录调控发生的,Atf3 是一种转录因子,可直接与 Cflar(编码抗细胞死亡蛋白 cFLIP 的基因)结合。cFLIP 可抑制 RIPK1 的活性,从而抑制下游的凋亡和坏死信号传导。这些发现共同阐明了 METTL3-ATF3-cFLIP 轴通过阻断 RIPK1 的活性在肠上皮细胞平衡调节中的重要作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Regeneration
Cell Regeneration Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
5.80
自引率
0.00%
发文量
42
审稿时长
35 days
期刊介绍: Cell Regeneration aims to provide a worldwide platform for researches on stem cells and regenerative biology to develop basic science and to foster its clinical translation in medicine. Cell Regeneration welcomes reports on novel discoveries, theories, methods, technologies, and products in the field of stem cells and regenerative research, the journal is interested, but not limited to the following topics: ◎ Embryonic stem cells ◎ Induced pluripotent stem cells ◎ Tissue-specific stem cells ◎ Tissue or organ regeneration ◎ Methodology ◎ Biomaterials and regeneration ◎ Clinical translation or application in medicine
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