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EFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death

Author

Listed:
  • Jiacheng Wu

    (Chinese Academy of Medical Sciences)

  • Xiaoqing Xu

    (Chinese Academy of Medical Sciences)

  • Jiaqi Duan

    (Chinese Academy of Medical Sciences)

  • Yangyang Chai

    (Chinese Academy of Medical Sciences)

  • Jiaying Song

    (Chinese Academy of Medical Sciences)

  • Dongsheng Gong

    (Chinese Academy of Medical Sciences)

  • Bingjing Wang

    (Chinese Academy of Medical Sciences)

  • Ye Hu

    (Chinese Academy of Medical Sciences
    Nankai University)

  • Taotao Han

    (Chinese Academy of Medical Sciences)

  • Yuanyuan Ding

    (Chinese Academy of Medical Sciences
    Chinese Academy of Medical Sciences)

  • Yin Liu

    (Chinese Academy of Medical Sciences)

  • Jingnan Li

    (Chinese Academy of Medical Sciences)

  • Xuetao Cao

    (Chinese Academy of Medical Sciences
    Nankai University)

Abstract

TNF acts as one pathogenic driver for inducing intestinal epithelial cell (IEC) death and substantial intestinal inflammation. How the IEC death is regulated to physiologically prevent intestinal inflammation needs further investigation. Here, we report that EF-hand domain-containing protein D2 (EFHD2), highly expressed in normal intestine tissues but decreased in intestinal biopsy samples of ulcerative colitis patients, protects intestinal epithelium from TNF-induced IEC apoptosis. EFHD2 inhibits TNF-induced apoptosis in primary IECs and intestinal organoids (enteroids). Mice deficient of Efhd2 in IECs exhibit excessive IEC death and exacerbated experimental colitis. Mechanistically, EFHD2 interacts with Cofilin and suppresses Cofilin phosphorylation, thus blocking TNF receptor I (TNFR1) internalization to inhibit IEC apoptosis and consequently protecting intestine from inflammation. Our findings deepen the understanding of EFHD2 as the key regulator of membrane receptor trafficking, providing insight into death receptor signals and autoinflammatory diseases.

Suggested Citation

  • Jiacheng Wu & Xiaoqing Xu & Jiaqi Duan & Yangyang Chai & Jiaying Song & Dongsheng Gong & Bingjing Wang & Ye Hu & Taotao Han & Yuanyuan Ding & Yin Liu & Jingnan Li & Xuetao Cao, 2024. "EFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45539-x
    DOI: 10.1038/s41467-024-45539-x
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    References listed on IDEAS

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