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<p>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.</p>

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SEL1L-HRD1 ER-associated degradation facilitates prohormone convertase 2 maturation and glucagon production in islet α cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月25日

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  • Wenzhen Zhu,
  • Linxiu Pan,
  • Xianwei Cui,
  • Anna Chiara Russo,
  • Rohit Ray,
  • Brent Pederson,
  • Xiaoqiong Wei,
  • Liangguang Leo Lin,
  • Mauricio Torres,
  • Hannah Hafner,
  • Brigid Gregg,
  • Neha Shrestha,
  • Chengyang Liu,
  • Ali Naji,
  • Peter Arvan,
  • Darleen A. Sandoval,
  • Iris Lindberg,
  • Ling Qi,
  • Rachel Byerley Reinert

摘要

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.