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

Saurabh Vig, Mijke Buitinga, Dieter Rondas, Inne Crevecoeur, Marc van Zandvoort, Etienne Waelkens, Decio L. Eizirik, Conny Gysemans, Pieter Baatsen, Chantal Mathieu, Lut Overbergh*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

38 Citations (Web of Science)

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-beta H1 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.

Original languageEnglish
Article number309
Pages (from-to)1-13
Number of pages13
JournalCell Death & Disease
Volume10
DOIs
Publication statusPublished - 5 Apr 2019

Keywords

  • ENDOPLASMIC-RETICULUM STRESS
  • COOH-TERMINAL DOMAIN
  • SURFACE GRP78
  • MONOCLONAL-ANTIBODY
  • PROTEIN BIP
  • CANCER
  • LIGATION
  • PROLIFERATION
  • ESTABLISHMENT
  • INFLAMMATION

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