ArticleThe Journal of clinical investigation2023
Integration of ER protein quality control mechanisms defines β cell function and ER architecture.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 46 citations in OpenAlex.
- Islet ultrastructure: past achievements and future directions.Diabetologia · 2026Review
- SEL1L-HRD1 ERAD-autophagy interplay maintains mitochondrial homeostasis in brown adipocytes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- SEL1L-HRD1 ER-associated degradation facilitates prohormone convertase 2 maturation and glucagon production in islet α cells.Nature communications · 2026Article
- Functional integrity of the SEL1L-HRD1 complex is critical for endoplasmic reticulum-associated degradation and organismal viability.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Advances in Research on Endoplasmic Reticulum-Associated Degradation Mechanisms in Neurodegenerative Diseases.Cellular and molecular neurobiology · 2026Review
- 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
- Neoepitopes at the crossroads of immunometabolism: metabolic remodeling of antigen presentation in type 1 diabetes.Frontiers in immunology · 2026Review
- SEL1L regulates ER homeostasis in Sertoli cells but is dispensable for their function.Molecular biology of the cell · 2025Article
- SEL1L-HRD1-mediated ERAD in mammals.Nature cell biology · 2025Review
- Endoplasmic reticulum (ER) protein degradation by ER-associated degradation and ER-phagy.Trends in cell biology · 2025Review
- VDAC1 is a target for pharmacologically induced insulin hypersecretion in β cells.Cell reports · 2025Article
- Coordinated Role of Autophagy and ERAD in Maintaining Neuroendocrine Function by Preventing Prohormone Aggregation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Review
- Exploring proinsulin proteostasis: insights into beta cell health and diabetes.Frontiers in molecular biosciences · 2025Review
- Microtubule acetylation and PERK activation facilitate eribulin-induced mitochondrial calcium accumulation and cell death.Cellular and molecular life sciences : CMLS · 2024Article
- HNF-1β alleviates podocyte injury in lupus nephritis by maintaining endoplasmic reticulum homeostasis.Lupus science & medicine · 2024Article
- Purkinje cell-specific deficiency in SEL1L-hrd1 endoplasmic reticulum-associated degradation causes progressive cerebellar ataxia in mice.JCI insight · 2024Article
- Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD.Nature communications · 2024Article
- Regulation of leptin signaling and diet-induced obesity by SEL1L-HRD1 ER-associated degradation in POMC expressing neurons.Nature communications · 2024Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
Three principal ER quality-control mechanisms, namely, the unfolded protein response, ER-associated degradation (ERAD), and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and organellar architecture in vivo is largely unclear. Here we report intricate crosstalk among the 3 pathways, centered around the SEL1L-HRD1 protein complex of ERAD, in the regulation of organellar organization in β cells. SEL1L-HRD1 ERAD deficiency in β cells triggers activation of autophagy, at least in part, via IRE1α (an endogenous ERAD substrate). In the absence of functional SEL1L-HRD1 ERAD, proinsulin is retained in the ER as high molecular weight conformers, which are subsequently cleared via ER-phagy. A combined loss of both SEL1L and autophagy in β cells leads to diabetes in mice shortly after weaning, with premature death by approximately 11 weeks of age, associated with marked ER retention of proinsulin and β cell loss. Using focused ion beam scanning electron microscopy powered by deep-learning automated image segmentation and 3D reconstruction, our data demonstrate a profound organellar restructuring with a massive expansion of ER volume and network in β cells lacking both SEL1L and autophagy. These data reveal at an unprecedented detail the intimate crosstalk among the 3 ER quality-control mechanisms in the dynamic regulation of organellar architecture and β cell function.
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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.