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SEL1L-HRD1 ER-associated degradation facilitates prohormone convertase 2 maturation and glucagon production in islet α cells
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SEL1L-HRD1 ER-associated degradation facilitates prohormone convertase 2 maturation and glucagon production in islet α cells
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Journal Article
SEL1L-HRD1 ER-associated degradation facilitates prohormone convertase 2 maturation and glucagon production in islet α cells
2026
Overview
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.
Glucagon production in pancreatic islet α cells requires the PC2 enzyme. Here, authors show SEL1L-HRD1 ERAD ensures proper maturation of PC2, highlighting an essential mechanism for maintaining glucagon production.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/51
/ 14/19
/ 14/28
/ 38/89
/ 64/60
/ Animals
/ Cells
/ Diabetes
/ Endoplasmic Reticulum - metabolism
/ Endoplasmic Reticulum-Associated Degradation
/ Glucagon
/ Glucagon-Secreting Cells - metabolism
/ Humanities and Social Sciences
/ Humans
/ Insulin
/ Intracellular Signaling Peptides and Proteins
/ Male
/ Mice
/ Pancreas
/ Peptides
/ Proprotein Convertase 2 - genetics
/ Proprotein Convertase 2 - metabolism
/ Proteins
/ Regulatory mechanisms (biology)
/ Science
/ Transmission electron microscopy
