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

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 Iwakiri, Junming Tang, Chenzhong Liao, Houzao Chen and Yajun Duan ()
Additional contact information
Ke Gong: University of Science and Technology of China
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

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51352-3

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