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

• Published in: Cell death & disease 2019-04, Vol.10 (4), p.309-309, Article 309
• Main Authors: Vig, Saurabh, Buitinga, Mijke, Rondas, Dieter, Crèvecoeur, Inne, van Zandvoort, Marc, Waelkens, Etienne, Eizirik, Decio L., Gysemans, Conny, Baatsen, Pieter, Mathieu, Chantal, Overbergh, Lut
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/2; 13/21; 13/31; 13/51; 13/89; 14/19; 14/28; 631/80/82/23; 631/80/86/2366; 82/29; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Bax protein; Beta cells; Biochemistry; Biomedical and Life Sciences; Blocking antibodies; Cancer; Caspase; Caspase-3; Cell Biology; Cell Culture; Cell death; Cell Line; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Membrane - ultrastructure; Cell surface; Cytokines; Cytokines - metabolism; Cytokines - pharmacology; Diabetes mellitus; Diabetes mellitus (insulin dependent); Endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Feedback; Feedback, Physiological - drug effects; Gene expression; Golgi apparatus; Golgi Apparatus - drug effects; Golgi Apparatus - metabolism; Golgi Apparatus - ultrastructure; Heat-Shock Proteins - antagonists & inhibitors; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Homeostasis; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; Humans; Immunology; Inflammation; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - immunology; Insulin-Secreting Cells - metabolism; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Life Sciences; Membrane proteins; Mice; Molecular Chaperones - metabolism; Pancreas; Proteins; Rats; Secretory vesicles; Signal transduction
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1518-0

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.