2025/11/18 by Anoop Arunagiri, Leena Haataja, Maroof Alam +12 · 1 voice
Medicine · Biochemistry, Genetics and Molecular Biology · #Pancreatic function and diabetes #Endoplasmic Reticulum Stress and Disease #Pancreatitis Pathology and Treatment
paper · pdf · doi:10.1172/jci187341
openalex created_date 2025/11/18 · openalex publication_date 2025/11/18 · openalex updated_date 2026/06/20
In pancreatic β cells, misfolded proinsulin is a substrate for ER-associated protein degradation (ERAD) via HRD1/SEL1L. Alternately, β cell HRD1 activity is reported to improve, or impair, insulin biogenesis. Further, while β cell SEL1L deficiency causes HRD1 hypofunction and diminishes islet insulin content, reports conflict as to whether β cell ERAD deficiency increases or decreases proinsulin levels. Here, we examined β cell-specific Hrd1-KO mice (chronic deficiency) and rodent (and human islet) β cells treated acutely with HRD1 inhibitor. β-Hrd1-KO mice developed diabetes with decreased islet proinsulin, yet a relative increase of misfolded proinsulin redistributed to the ER. They also showed upregulated biochemical markers of β cell ER stress and autophagy, electron microscopy evidence of ER enlargement and decreased insulin granule content, and increased glucagon-positive islet cells. Misfolded proinsulin was also increased in islets treated with inhibitors of lysosomal degradation. Preceding any loss of total proinsulin, acute HRD1 inhibition triggered increased nonnative proinsulin, increased phospho-eIF2α with inhibited proinsulin synthesis, and increased LC3b-II (the abundance of which requires expression of ΣR1). We posit a subset of proinsulin molecules undergo HRD1-mediated disposal. When HRD1 is unavailable, misfolded proinsulin accumulates, accompanied by increased phospho-eIF2α that limits further proinsulin synthesis, plus ΣR1-dependent autophagy activation, ultimately lowering steady-state β cell proinsulin (and insulin) levels and triggering diabetes.