Abstract
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 observe a progressive decline in stimulated glucagon secretion and a reduction in pancreatic glucagon content. Mechanistically, we find that endogenous proPC2 is a substrate of SEL1L-HRD1 ERAD, and that degradation of misfolded proPC2 ensures the maturation of activation-competent proPC2 protein in the ER. Here, we identify ERAD as a regulator of PC2 biology and an essential mechanism for maintaining α cell function.
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Acknowledgements
We thank Dr. Ernesto Bernal-Mizrachi for sharing αTC(1-6) cells; Dr. Yewei Ji, Dr. Leena Haataja, Jianing Zhang, Elise Corden, and Steve Lentz for experimental support; and all other members of the Qi and Arvan laboratories for comments and technical assistance. This work was completed with the assistance of NIH-supported core facilities, including the Microscopy, Imaging and Cellular Physiology Core (MICPC) and Islet Isolation Laboratory supported by the National Institute of Diabetes, Digestive, and Kidney (NIDDK)-funded Michigan Diabetes Research Center (P30DK020572 and Shared Instrument Grant S10OD28612-01-A1), the University of Michigan Vision Research Center Morphology and Imaging Core supported by the National Eye Institute (P30EY007003), the Tissue and Molecular Pathology Shared Resource supported by the National Cancer Institute (P30CA04659229), and the University of Michigan Biomedical Research Core Facilities Microscopy Core. This manuscript used human islets acquired from the University of Pennsylvania Islet Transplant Center in collaboration with the Human Pancreas Analysis Program (HPAP-RRID:SCR_016202), a Human Islet Research Network (RRID:SCR_014393) consortium (UC4DK112217), and the Integrated Islet Distribution Program (IIDP) (RRID:SCR_014387) through City of Hope (UC4DK098085), supported by Beckman Research Center grant 10028044 (to A.N.). We thank the human islet donors and their families for their generous contribution. This work was supported by R24DK110973 (to P.A.), R01DK11174 and 2-SRA-2018-539-A-B (to P.A. and L.Q.), R01DK121995 (to D.A.S), R01DK137794 and R35GM130292 (to L.Q.), and 5T32DK007245 and K08DK129719 (to R.B.R.).
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W.Z., L.P., X.C., A.C.R., R.R., B.P., X.W., L.L.L., M.T., H.H., B.G., and R.B.R. performed experiments that were designed by W.Z., L.P., L.Q., and R.B.R.; N.S. made the initial crosses of knockout mice and provided experimental support and helpful discussion; C.L., A.N., P.A., D.S., and I.L. provided key reagents and helpful discussion; L.Q. and R.B.R. supervised the project and wrote the manuscript. All other authors edited and approved the manuscript.
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Zhu, W., Pan, L., Cui, X. et al. SEL1L-HRD1 ER-associated degradation facilitates prohormone convertase 2 maturation and glucagon production in islet α cells. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69928-6
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DOI: https://doi.org/10.1038/s41467-026-69928-6
