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Cell Death Dis. 2019 Apr 5;10(4):309. doi: 10.1038/s41419-019-1518-0.

Cytokine-induced translocation of GRP78 to the plasma membrane triggers a pro-apoptotic feedback loop in pancreatic beta cells.

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Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
Department of Molecular Cell Biology and School for Nutrition and Translational Research in Metabolism NUTRIM, Maastricht University, Maastricht, The Netherlands.
Laboratory of Protein Phosphorylation and Proteomics, KU Leuven, Leuven, Belgium.
SyBioMa, KU Leuven, Leuven, Belgium.
ULB Center for Diabetes Research, Universite Libre de Bruxelles, Brussels, Belgium.
Electron Microscopy Platform of VIB Bio Imaging Core at KU Leuven and VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.


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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