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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.

Author information

1
Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
2
Department of Molecular Cell Biology and School for Nutrition and Translational Research in Metabolism NUTRIM, Maastricht University, Maastricht, The Netherlands.
3
Laboratory of Protein Phosphorylation and Proteomics, KU Leuven, Leuven, Belgium.
4
SyBioMa, KU Leuven, Leuven, Belgium.
5
ULB Center for Diabetes Research, Universite Libre de Bruxelles, Brussels, Belgium.
6
Electron Microscopy Platform of VIB Bio Imaging Core at KU Leuven and VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
7
Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium. lutgart.overbergh@kuleuven.be.

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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