ArticleCell death & disease2019
Cytokine-induced translocation of GRP78 to the plasma membrane triggers a pro-apoptotic feedback loop in pancreatic beta cells.
Article in Cell death & disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 91 citations in OpenAlex.
- Diabetes, Protein Misfolding, and Heat Stress: Molecular Insights and Translational Perspectives.TH open : companion journal to thrombosis and haemostasis · 2026Review
- Enhancing Cytosolic Internalization of [International journal of molecular sciences · 2025Article
- Article
- The interplay between endoplasmic reticulum stress and inflammation in multiple sclerosis.Scientific reports · 2025Article
- Anti-Müllerian hormone binds heat shock protein glucose-regulated protein 78 in human follicular fluid.Journal of assisted reproduction and genetics · 2025Article
- GRP78 as a potential therapeutic target in cancer treatment: an updated review of its role in chemoradiotherapy resistance of cancer cells.Medical oncology (Northwood, London, England) · 2025Review
- Circular RNAs in Blood and Its Clinical Relevance.Advances in experimental medicine and biology · 2025Review
- Establishment of a non-alcoholic fatty liver disease model by high fat diet in adult zebrafish.Animal models and experimental medicine · 2024Article
- Glucose-Regulated Protein 78, via Releasing β-Catenin from Adherens Junctions, Facilitates Its Interaction with STAT3 in Mediating Retinal Neovascularization.The American journal of pathology · 2024Article
- The Functions of SARS-CoV-2 Receptors in Diabetes-Related Severe COVID-19.International journal of molecular sciences · 2024Review
- Intake of Special Amino Acids Mixture Leads to Blunted Murine Colon Cancer Growth In Vitro and In Vivo.Cells · 2024Article
- CD4+ T Cells From Individuals With Type 1 Diabetes Respond to a Novel Class of Deamidated Peptides Formed in Pancreatic Islets.Diabetes · 2024Article
- Metal-Binding Proteins Cross-Linking with Endoplasmic Reticulum Stress in Cardiovascular Diseases.Journal of cardiovascular development and disease · 2023Review
- The therapeutic mavericks: Potent immunomodulating chaperones capable of treating human diseases.Journal of cellular and molecular medicine · 2023Review
- Secreted glucose regulated protein78 ameliorates DSS-induced mouse colitis.Frontiers in immunology · 2023Article
- Direct interaction of the molecular chaperone GRP78/BiP with the Newcastle disease virus hemagglutinin-neuraminidase protein plays a vital role in viral attachment to and infection of culture cells.Frontiers in immunology · 2023Article
- Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation.Cell death discovery · 2022Article
- Siah2-GRP78 interaction regulates ROS and provides a proliferative advantage to Helicobacter pylori-infected gastric epithelial cancer cells.Cellular and molecular life sciences : CMLS · 2022Article
- Sigma-1 receptor activity in primary sensory neurons is a critical driver of neuropathic pain.Gene therapy · 2022Article
- ER stress-induced cell death proceeds independently of the TRAIL-R2 signaling axis in pancreatic β cells.Cell death discovery · 2022Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The 78-kDa glucose-regulated protein (GRP78) is an ubiquitously expressed endoplasmic reticulum chaperone, with a central role in maintaining protein homeostasis. Recently, an alternative role for GRP78 under stress conditions has been proposed, with stress-induced extracellular secretion and translocation of GRP78 to the cell surface where it acts as a multifunctional signaling receptor. Here we demonstrate translocation of GRP78 to the surface of human EndoC-βH1 cells and primary human islets upon cytokine exposure, in analogy to observations in rodent INS-1E and MIN6 beta cell lines. We show that GRP78 is shuttled via the anterograde secretory pathway, through the Golgi complex and secretory granules, and identify the DNAJ homolog subfamily C member 3 (DNAJC3) as a GRP78-interacting protein that facilitates its membrane translocation. Evaluation of downstream signaling pathways, using N- and C-terminal anti-GRP78 blocking antibodies, demonstrates that both GRP78 signaling domains initiate pro-apoptotic signaling cascades in beta cells. Extracellular GRP78 itself is identified as a ligand for cell surface GRP78 (sGRP78), increasing caspase 3/7 activity and cell death upon binding, which is accompanied by enhanced Chop and Bax mRNA expression. These results suggest that inflammatory cytokines induce a self-destructive pro-apoptotic feedback loop through the secretion and membrane translocation of GRP78. This proapoptotic function distinguishes the role of sGRP78 in beta cells from its reported anti-apoptotic and proliferative role in cancer cells, opening the road for the use of compounds that block sGRP78 as potential beta cell-preserving therapies in type 1 diabetes.
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