Zhu Wenzhen, Pan Linxiu, Cui Xianwei, Russo Anna Chiara, Ray Rohit, Pederson Brent, Wei Xiaoqiong, Lin Liangguang Leo, Hafner Hannah, Gregg Brigid, Shrestha Neha, Liu Chengyang, Naji Ali, Arvan Peter, Sandoval Darleen A, Lindberg Iris, Qi Ling, Reinert Rachel B
Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Present address: Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
bioRxiv. 2025 Mar 20:2025.03.20.644437. doi: 10.1101/2025.03.20.644437.
Proteolytic cleavage of proglucagon by prohormone convertase 2 (PC2) is required for islet α cells to generate glucagon. However, the regulatory mechanisms underlying this process remain largely unclear. Here, we report that SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD), a highly conserved protein quality control system responsible for clearing misfolded proteins from the ER, plays a key role in glucagon production by regulating turnover of the nascent proform of the PC2 enzyme (proPC2). Using a mouse model with SEL1L deletion in proglucagon-expressing cells, we observed a progressive decline in stimulated glucagon secretion and a reduction in pancreatic glucagon content. Mechanistically, we found that endogenous proPC2 is a substrate of SEL1L-HRD1 ERAD, and that degradation of misfolded proPC2 ensures the maturation of activation-competent proPC2 protein. These findings identify ERAD as a novel regulator of PC2 biology and an essential mechanism for maintaining α cell function.
胰岛α细胞生成胰高血糖素需要激素原转化酶2（PC2）对前胰高血糖素进行蛋白水解切割。然而，这一过程背后的调控机制在很大程度上仍不清楚。在此，我们报告称，SEL1L-HRD1内质网（ER）相关降解（ERAD），一种负责从内质网清除错误折叠蛋白的高度保守的蛋白质质量控制系统，通过调节PC2酶新生前体形式（前PC2）的周转，在胰高血糖素产生中起关键作用。使用在表达前胰高血糖素的细胞中缺失SEL1L的小鼠模型，我们观察到刺激的胰高血糖素分泌逐渐下降，胰腺中胰高血糖素含量降低。从机制上讲，我们发现内源性前PC2是SEL1L-HRD1 ERAD的底物，错误折叠的前PC2的降解确保了具有激活能力的前PC2蛋白的成熟。这些发现确定ERAD是PC2生物学的一种新型调节因子，也是维持α细胞功能的重要机制。
