ArticleProceedings of the National Academy of Sciences of the United States of America2011
Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 179 papers, 1 of them a synthesis that pooled it.
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Who cites it
179 citing papers in PubMed, 1 synthesis or guideline pooled it, 267 citations in OpenAlex.
- Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer.Nature genetics · 2014Pooled it
- Targeting the IRE1α/XBP1 pathway in type 2 diabetes mellitus: from ER stress signaling to therapeutic opportunity.Molecular biology reports · 2026Review
- Dual IRE1 targets: Determinants of the cell fate?The FEBS journal · 2026Review
- Hac1-independent functions of Ire1 drive morphogenesis in Candida albicans through distinct transcriptional programs.Journal of cell science · 2026Article
- A surviving beta cell subpopulation enriched in patients with T1D.bioRxiv : the preprint server for biology · 2026Article
- Single-cell RNA-seq and in vitro study reveal Fusobacterium nucleatum impairs β-cell identity in type 2 diabetes via the NF-κB-CDKN1C axis.Journal of translational medicine · 2026Article
- Defining the role of β-cell IRE1α/XBP1 pathway and its gene regulatory network components in non-obese diabetic mice.Nature communications · 2025Article
- Reductive stress: The key pathway in metabolic disorders induced by overnutrition.Journal of advanced research · 2025Review
- Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B.Brain : a journal of neurology · 2025Article
- Identification of a Selective Pharmacologic IRE1/XBP1s Activator with Enhanced Tissue Exposure.ACS chemical biology · 2025Article
- Ceramide mediates cell-to-cell ER stress transmission by modulating membrane fluidity.The Journal of cell biology · 2025Article
- Mettl3 deficiency leads to impaired insulin secretion via regulating Ire1a of mature β-cells in mice.Scientific reports · 2025Article
- Less is better: various means to reduce protein load in the endoplasmic reticulum.The FEBS journal · 2025Review
- Gene module reconstruction identifies cellular differentiation processes and the regulatory logic of specialized secretion in zebrafish.Developmental cell · 2025Article
- E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β cells.Genes & development · 2025Article
- Hyperglucagonemia and glucagon hypersecretion in early type 2 diabetes result from multifaceted dysregulation of pancreatic mouse α-cells.Pflugers Archiv : European journal of physiology · 2025Article
- Type 2 Diabetes Mellitus: New Pathogenetic Mechanisms, Treatment and the Most Important Complications.International journal of molecular sciences · 2025Review
- Roles of X-box binding protein 1 in liver pathogenesis.Clinical and molecular hepatology · 2025Review
- Review
- Protein Glycosylation Patterns Shaped By the IRE1-XBP1s Arm of the Unfolded Protein Response.Israel journal of chemistry · 2024Article
119 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
As a key regulator of the unfolded protein response, the transcription factor XBP1 activates genes in protein secretory pathways and is required for the development of certain secretory cells. To elucidate the function of XBP1 in pancreatic β-cells, we generated β-cell-specific XBP1 mutant mice. Xbp1(f/f);RIP-cre mice displayed modest hyperglycemia and glucose intolerance resulting from decreased insulin secretion from β-cells. Ablation of XBP1 markedly decreased the number of insulin granules in β-cells, impaired proinsulin processing, increased the serum proinsulin:insulin ratio, blunted glucose-stimulated insulin secretion, and inhibited cell proliferation. Notably, XBP1 deficiency not only compromised the endoplasmic reticulum stress response in β-cells but also caused constitutive hyperactivation of its upstream activator, IRE1α, which could degrade a subset of mRNAs encoding proinsulin-processing enzymes. Hence, the combined effects of XBP1 deficiency on the canonical unfolded protein response and its negative feedback activation of IRE1α caused β-cell dysfunction in XBP1 mutant mice. These results demonstrate that IRE1α has dual and opposing roles in β-cells, and that a precisely regulated feedback circuit involving IRE1α and its product XBP1s is required to achieve optimal insulin secretion and glucose control.
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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.