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

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

  • Cell Regen. 2024 Aug 2;13(1):14. doi: 10.1186/s13619-024-00197-8.
Meimei Huang # 1 2,  Xiaodan Wang # 1,  Mengxian Zhang 1,  Yuan Liu 3,  Ye-Guang Chen 4 5 6
Affiliations

Affiliations

  • 1 The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 2 Guangzhou National Laboratory, Guangzhou, 510700, China.
  • 3 The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China. liu-yuan@mail.tsinghua.edu.cn.
  • 4 The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China. ygchen@tsinghua.edu.cn.
  • 5 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. ygchen@tsinghua.edu.cn.
  • 6 Guangzhou National Laboratory, Guangzhou, 510700, China. ygchen@tsinghua.edu.cn.
  • # Contributed equally.
PMID: 39093347 DOI: 10.1186/s13619-024-00197-8
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.

Keywords

Mettl3; Apoptosis; Intestinal homeostasis; Necroptosis; RIPK1; m6A modification.

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