Peptide Binding Glucose Regulated Protein 78 Improves Type 1 Diabetes by Preventing Pancreatic β Cell Apoptosis

Raiter, Annat; Tenenbaum, Ariel; Yackobovitch‐Gavan, Michal; Battler, Alexander; Hardy, Britta

doi:10.1055/s-0035-1569356

Cited by 3 publications

(1 citation statement)

References 37 publications

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“…34 Moreover, AdoPep1 also inhibits hypoxia-induced apoptosis in cardiomyocytes and protects cardiac cells during myocardial ischaemia, 50 and also prevents pancreatic β-cells from type 1 diabetes-induced apoptosis. 51 Another compound, BIX (BiP Inducer X), is able to induce the expression of Grp78 through the ATF6 pathway. 52 BIX has been shown to protect neuroblastoma cells from ER stress-induced cell death and to decrease infarct size in rodents following various models of cerebral ischaemia.…”

Section: Discussionmentioning

confidence: 99%

Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death

et al. 2017

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The unfolded protein response (UPR) is an endoplasmic reticulum (ER) -related stress conserved pathway that aims to protect cells from being overwhelmed. However, when prolonged, UPR activation converts to a death signal, which relies on its PERK-eIF2α branch. Overactivation of the UPR has been implicated in many neurological diseases, including cerebral ischaemia. Here, by using an in vivo thromboembolic model of stroke on transgenic ER stress-reporter mice and neuronal in vitro models of ischaemia, we demonstrate that ischaemic stress leads to the deleterious activation of the PERK branch of the UPR. Moreover, we show that the serine protease tissue-type plasminogen activator (tPA) can bind to cell surface Grp78 (78 kD glucose-regulated protein), leading to a decrease of the PERK pathway activation, thus a decrease of the deleterious factor CHOP, and finally promotes neuroprotection. Altogether, this work highlights a new role and a therapeutic potential of the chaperone protein Grp78 as a membrane receptor of tPA capable to prevent from ER stress overactivation.

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Section: Discussionmentioning

confidence: 99%

Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death

et al. 2017

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

et al. 2019

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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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Cell surface expression of 78-kDa glucose-regulated protein (GRP78) mediates diabetic nephropathy

Krieken

Mehta

Wang

et al. 2019

Journal of Biological Chemistry

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The 78-kDa glucose-regulated protein (GRP78) is a well-established endoplasmic reticulum (ER)-resident chaperone that maintains protein homeostasis and regulates the unfolded protein response. Under conditions of ER stress, GRP78 is also expressed at the cell surface and implicated in tumorigenesis, immunity, and cellular signaling events. The role of cell surfaceassociated GRP78 (csGRP78) in the pathogenesis of diabetic nephropathy has not yet been defined. Here we explored the role of csGRP78 in regulating high glucose (HG)-induced profibrotic AKT Ser/Thr kinase (AKT) signaling and up-regulation of extracellular matrix proteins. Using primary kidney mesangial cells, we show that HG treatment, but not the osmotic control mannitol, induces csGRP78 expression through an ER stress-dependent mechanism. We found that csGRP78, known to be located on the outer membrane leaflet, interacts with the transmembrane protein integrin ␤1 and activates focal adhesion kinase and downstream PI3K/AKT signaling. Localization of GRP78 at the cell surface and its interaction with integrin ␤1 were also required for extracellular matrix protein synthesis in response to HG. Surprisingly, both the N and C termini of csGRP78 were necessary for this profibrotic response. Increased localization of GRP78 at the plasma membrane was also found in the glomerular mesangial area of type 1 diabetic mice in two different models (streptozotocin-induced and Akita). In freshly isolated glomeruli from Akita mice, csGRP78 colocalized with the mesangial cell surface marker ␣8-integrin. In conclusion, our work reveals a role for csGRP78 in HG-induced profibrotic responses in mesangial cells, informing a potential approach to treating diabetic nephropathy. Diabetic nephropathy (DN) 3 is a major complication of diabetes and the leading cause of kidney failure in North America.

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Peptide Binding Glucose Regulated Protein 78 Improves Type 1 Diabetes by Preventing Pancreatic β Cell Apoptosis

Abstract: We demonstrate that administration of the peptide ADoPep to diabetic mice improved type 1 diabetes by preventing pancreatic β cell apoptosis.

Cited by 3 publications

References 37 publications

Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death

Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death

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

Cell surface expression of 78-kDa glucose-regulated protein (GRP78) mediates diabetic nephropathy

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