ArticleMolecular biology of the cell2015
PDI reductase acts on Akita mutant proinsulin to initiate retrotranslocation along the Hrd1/Sel1L-p97 axis.
Article in Molecular biology of the cell, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 47 citations in OpenAlex.
- Limiting ER-associated degradation capacity triggers acute and chronic effects on insulin biosynthesis.The Journal of clinical investigation · 2026Article
- The role of ER-associated degradation and ER-phagy in health and disease.Signal transduction and targeted therapy · 2026Review
- The beneficial effect of hepatic ER stress-associated protein PDI on obesity-associated glucose dysregulation.Nutrition & metabolism · 2025Article
- Thiol Isomerases: Enzymatic Mechanisms, Models of Oxidation, and Antagonism by Galloylated Polyphenols.Antioxidants (Basel, Switzerland) · 2025Review
- Endoplasmic reticulum (ER) protein degradation by ER-associated degradation and ER-phagy.Trends in cell biology · 2025Review
- Exploring proinsulin proteostasis: insights into beta cell health and diabetes.Frontiers in molecular biosciences · 2025Review
- Molecular basis of TMED9 oligomerization and entrapment of misfolded protein cargo in the early secretory pathway.Science advances · 2024Article
- Casting Light on the Janus-Faced HMG-CoA Reductase Degradation Protein 1: A Comprehensive Review of Its Dualistic Impact on Apoptosis in Various Diseases.Molecular neurobiology · 2024Review
- Article
- ER exit in physiology and disease.Frontiers in molecular biosciences · 2024Review
- Protein quality control and aggregation in the endoplasmic reticulum: From basic to bedside.Frontiers in cell and developmental biology · 2023Review
- Endoplasmic Reticulum-Associated Protein Degradation.Cold Spring Harbor perspectives in biology · 2022Review
- ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum.Physiological reviews · 2022Review
- Review
- Normal and defective pathways in biogenesis and maintenance of the insulin storage pool.The Journal of clinical investigation · 2021Review
- SUMOylation of Pdia3 exacerbates proinsulin misfolding and ER stress in pancreatic beta cells.Journal of molecular medicine (Berlin, Germany) · 2020Article
- Article
- Review
- Endoplasmic Reticulum Protein Quality Control in β Cells.Seminars in cell & developmental biology · 2020Review
- Non-native proteins inhibit the ER oxidoreductin 1 (Ero1)-protein disulfide-isomerase relay when protein folding capacity is exceeded.The Journal of biological chemistry · 2020Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
In mutant INS gene-induced diabetes of youth (MIDY), characterized by insulin deficiency, MIDY proinsulin mutants misfold and fail to exit the endoplasmic reticulum (ER). Moreover, these mutants bind and block ER exit of wild-type (WT) proinsulin, inhibiting insulin production. The ultimate fate of ER-entrapped MIDY mutants is unclear, but previous studies implicated ER-associated degradation (ERAD), a pathway that retrotranslocates misfolded ER proteins to the cytosol for proteasomal degradation. Here we establish key ERAD machinery components used to triage the Akita proinsulin mutant, including the Hrd1-Sel1L membrane complex, which conducts Akita proinsulin from the ER lumen to the cytosol, and the p97 ATPase, which couples the cytosolic arrival of proinsulin with its proteasomal degradation. Surprisingly, we find that protein disulfide isomerase (PDI), the major protein oxidase of the ER lumen, engages Akita proinsulin in a novel way, reducing proinsulin disulfide bonds and priming the Akita protein for ERAD. Efficient PDI engagement of Akita proinsulin appears linked to the availability of Hrd1, suggesting that retrotranslocation is coordinated on the lumenal side of the ER membrane. We believe that, in principle, this form of diabetes could be alleviated by enhancing the targeting of MIDY mutants for ERAD to restore WT insulin production.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.