SEL1L-HRD1 ER-Associated Degradation Facilitates Prohormone Convertase 2 Maturation and Glucagon Production in Islet α Cells

Zhu, W.; Pan, L.; Cui, X.; Russo, A. C.; Ray, R.; Pederson, B.; Wei, X.; Lin, L. L.; Hafner, H.; Gregg, B.; Shrestha, N.; Liu, C.; Naji, A.; Arvan, P.; Sandoval, D.; Lindberg, I.; Qi, L.; Reinert, R. B.

doi:10.1101/2025.03.20.644437

bioRxiv · 10.1101/2025.03.20.644437

SEL1L-HRD1 ER-Associated Degradation Facilitates Prohormone Convertase 2 Maturation and Glucagon Production in Islet α Cells

Zhu, W.·Pan, L.·Cui, X.·Russo, A. C.·Ray, R.·Pederson, B.·Wei, X.·Lin, L. L.·Hafner, H.·Gregg, B.·Shrestha, N.·Liu, C.·Naji, A.·Arvan, P.·Sandoval, D.·Lindberg, I.·Qi, L.·Reinert, R. B.

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Abstract

Proteolytic cleavage of proglucagon by prohormone convertase 2 (PC2) is required for islet 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 cell function.

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Zhu, W., Pan, L., Cui, X., Russo, A. C., Ray, R., Pederson, B., Wei, X., Lin, L. L., Hafner, H., Gregg, B., Shrestha, N., Liu, C., Naji, A., Arvan, P., Sandoval, D., Lindberg, I., Qi, L., Reinert, R. B.. 2025-03-20. SEL1L-HRD1 ER-Associated Degradation Facilitates Prohormone Convertase 2 Maturation and Glucagon Production in Islet α Cells. https://doi.org/10.1101/2025.03.20.644437

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