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

Gong, Ke1,2,3; Xue, Chao4; Feng, Zian1; Pan, Ruru1; Wang, Mengyao3; Chen, Shasha3; Chen, Yuanli3; Guan, Yudong5,6; Dai, Lingyun5,6; Zhang, Shuang3; Jiang, Liwei7; Li, Ling7; Wang, Bei8; Yin, Zequn1; Ma, Likun1; Iwakiri, Yasuko9; Tang, Junming2; Liao, Chenzhong3; Chen, Houzao10; Duan, Yajun1

2024-08-10

10.1038/s41467-024-51352-3

NATURE COMMUNICATIONS   影响因子和分区

2041-1723

["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.","Glucagon-like peptide 1 (GLP1) is processed and cleaved from proglucagon to stimulate insulin secretion. Here, authors show that Nogo-B interacts with proglucagon to retain it on the ER, thereby inhibiting PCSK1-mediated cleavage of proglucagon and secretion of GLP1."]

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英语

其他

National Natural Science Foundation of China (National Science Foundation of China)["U22A20272","82173807","82304503","82300516"] ; China NSFC[RCYX20210706092040048]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:001288373600004

NATURE PORTFOLIO

Web of Science

1.Univ Sci & Technol China, Affiliated Hosp USTC 1, Dept Cardiol, Div Life Sci & Med, Hefei, Anhui, Peoples R China
2.Hubei Univ Med, Fac Basic Med Sci, Dept Physiol, Hubei Key Lab Embryon Stem Cell Res, Shiyan, Peoples R China
3.Hefei Univ Technol, Anhui Higher Educ Inst, Key Lab Metab & Regulat Major Dis, Hefei, Anhui, Peoples R China
4.Nankai Univ, Coll Life Sci, Minist Educ, Key Lab Bioact Mat, Tianjin, Peoples R China
5.Southern Univ Sci & Technol, Dept Geriatr, Shenzhen, Guangdong, Peoples R China
6.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Shenzhen Clin Res Ctr Geriatr, Shenzhen, Guangdong, Peoples R China
7.Chinese Acad Sci, Inst Hlth & Med Technol, Hefei Inst Phys Sci, Lab Immunoengn, Hefei, Anhui, Peoples R China
8.China Japan Friendship Hosp, Dept Pathol, Beijing, Peoples R China
9.Yale Univ, Sch Med, Sect Digest Dis, New Haven, CT USA
10.Chinese Acad Med Sci & Peking Union Med Coll, Inst Basic Med Sci, Dept Biochem & Mol Biol, State Key Lab Med Mol Biol, Beijing, Peoples R China

Gong, Ke,Xue, Chao,Feng, Zian,et al. Intestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage[J]. NATURE COMMUNICATIONS,2024,15(1).

Gong, Ke.,Xue, Chao.,Feng, Zian.,Pan, Ruru.,Wang, Mengyao.,...&Duan, Yajun.(2024).Intestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage.NATURE COMMUNICATIONS,15(1).

Gong, Ke,et al."Intestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage".NATURE COMMUNICATIONS 15.1(2024).