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Intestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage

Author

Listed:
  • Ke Gong

    (University of Science and Technology of China
    Hubei University of Medicine
    Hefei University of Technology)

  • Chao Xue

    (Nankai University)

  • Zian Feng

    (University of Science and Technology of China)

  • Ruru Pan

    (University of Science and Technology of China)

  • Mengyao Wang

    (Hefei University of Technology)

  • Shasha Chen

    (Hefei University of Technology)

  • Yuanli Chen

    (Hefei University of Technology)

  • Yudong Guan

    (Shenzhen)

  • Lingyun Dai

    (Shenzhen)

  • Shuang Zhang

    (Hefei University of Technology)

  • Liwei Jiang

    (Chinese Academy of Sciences)

  • Ling Li

    (Chinese Academy of Sciences)

  • Bei Wang

    (China-Japan Friendship Hospital)

  • Zequn Yin

    (University of Science and Technology of China)

  • Likun Ma

    (University of Science and Technology of China)

  • Yasuko Iwakiri

    (Yale University School of Medicine)

  • Junming Tang

    (Hubei University of Medicine)

  • Chenzhong Liao

    (Hefei University of Technology)

  • Houzao Chen

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Yajun Duan

    (University of Science and Technology of China)

Abstract

Glucagon-like peptide 1 (GLP1), which is mainly processed and cleaved from proglucagon in enteroendocrine cells (EECs) of the intestinal tract, acts on the GLP1 receptor in pancreatic cells to stimulate insulin secretion and to inhibit glucagon secretion. However, GLP1 processing is not fully understood. Here, we show that reticulon 4B (Nogo-B), an endoplasmic reticulum (ER)-resident protein, interacts with the major proglucagon fragment of proglucagon to retain proglucagon on the ER, thereby inhibiting PCSK1-mediated cleavage of proglucagon in the Golgi. Intestinal Nogo-B knockout in male type 2 diabetes mellitus (T2DM) mice increases GLP1 and insulin levels and decreases glucagon levels, thereby alleviating pancreatic injury and insulin resistance. Finally, we identify aberrantly elevated Nogo-B expression and inhibited proglucagon cleavage in EECs from diabetic patients. Our study reveals the subcellular regulatory processes involving Nogo-B during GLP1 production and suggests intestinal Nogo-B as a potential therapeutic target for T2DM.

Suggested Citation

  • Ke Gong & Chao Xue & Zian Feng & Ruru Pan & Mengyao Wang & Shasha Chen & Yuanli Chen & Yudong Guan & Lingyun Dai & Shuang Zhang & Liwei Jiang & Ling Li & Bei Wang & Zequn Yin & Likun Ma & Yasuko Iwaki, 2024. "Intestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51352-3
    DOI: 10.1038/s41467-024-51352-3
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    References listed on IDEAS

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    1. Tadzia GrandPré & Fumio Nakamura & Timothy Vartanian & Stephen M. Strittmatter, 2000. "Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein," Nature, Nature, vol. 403(6768), pages 439-444, January.
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