Limiting ER-associated degradation capacity triggers acute and chronic effects on insulin biosynthesis

Anoop Arunagiri; Leena Haataja; Maroof Alam; Noah F. Gleason; Emma Mastroianni; Chao-Yin Cheng; Sami Bazzi Onton; Jeffrey Knupp; Ibrahim Metawea; Anis Hassan; Dennis Larkin; Deyu Fang; Billy Tsai; Ling Qi; Peter Arvan

doi:10.1172/JCI187341

Limiting ER-associated degradation capacity triggers acute and chronic effects on insulin biosynthesis

Anoop Arunagiri,¹ Leena Haataja,¹ Maroof Alam,¹ Noah F. Gleason,¹ Emma Mastroianni,¹ Chao-Yin Cheng,² Sami Bazzi Onton,¹ Jeffrey Knupp,² Ibrahim Metawea,¹ Anis Hassan,¹ Dennis Larkin,¹ Deyu Fang,³ Billy Tsai,² Ling Qi,⁴ and Peter Arvan¹

Published November 18, 2025 - More info

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Abstract

In pancreatic β-cells, misfolded proinsulin is a substrate for Endoplasmic Reticulum-Associated protein Degradation (ERAD) via HRD1/SEL1L. β-cell HRD1 activity is alternately 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’ve examined β-cell-specific Hrd1-KO mice (chronic deficiency), plus 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 re-distributed to the ER; upregulated biochemical markers of β-cell ER stress and autophagy; electron microscopic 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-eIF2ɑ with inhibited proinsulin synthesis, and increased LC3b-II (the abundance of which requires expression of SigmaR1). We posit a subset of proinsulin molecules undergoes HRD1-mediated disposal. When HRD1 is unavailable, misfolded proinsulin accumulates, accompanied by increased phospho-eIF2ɑ that limits further proinsulin synthesis, plus SigmaR1-dependent autophagy activation, ultimately lowering steady-state β-cell proinsulin (and insulin) levels — triggering diabetes.

Limiting ER-associated degradation capacity triggers acute and chronic effects on insulin biosynthesis

Anoop Arunagiri,¹ Leena Haataja,¹ Maroof Alam,¹ Noah F. Gleason,¹ Emma Mastroianni,¹ Chao-Yin Cheng,² Sami Bazzi Onton,¹ Jeffrey Knupp,² Ibrahim Metawea,¹ Anis Hassan,¹ Dennis Larkin,¹ Deyu Fang,³ Billy Tsai,² Ling Qi,⁴ and Peter Arvan¹

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Limiting ER-associated degradation capacity triggers acute and chronic effects on insulin biosynthesis

Anoop Arunagiri,1 Leena Haataja,1 Maroof Alam,1 Noah F. Gleason,1 Emma Mastroianni,1 Chao-Yin Cheng,2 Sami Bazzi Onton,1 Jeffrey Knupp,2 Ibrahim Metawea,1 Anis Hassan,1 Dennis Larkin,1 Deyu Fang,3 Billy Tsai,2 Ling Qi,4 and Peter Arvan1

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Anoop Arunagiri,¹ Leena Haataja,¹ Maroof Alam,¹ Noah F. Gleason,¹ Emma Mastroianni,¹ Chao-Yin Cheng,² Sami Bazzi Onton,¹ Jeffrey Knupp,² Ibrahim Metawea,¹ Anis Hassan,¹ Dennis Larkin,¹ Deyu Fang,³ Billy Tsai,² Ling Qi,⁴ and Peter Arvan¹