Format

Send to

Choose Destination
J Biol Chem. 2017 Sep 8;292(36):14977-14988. doi: 10.1074/jbc.M116.769877. Epub 2017 Jul 11.

Pancreatic β-cell protection from inflammatory stress by the endoplasmic reticulum proteins thrombospondin 1 and mesencephalic astrocyte-derived neutrotrophic factor (MANF).

Author information

1
From the Université Libre de Bruxelles Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, 1070 Brussels, Belgium.
2
the Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
3
the Department of Endocrinology and Metabolism, University of Pisa, 56100 Pisa, Italy, and.
4
From the Université Libre de Bruxelles Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, 1070 Brussels, Belgium, mcnop@ulb.ac.be.
5
the Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium.

Abstract

Cytokine-induced endoplasmic reticulum (ER) stress is one of the molecular mechanisms underlying pancreatic β-cell demise in type 1 diabetes. Thrombospondin 1 (THBS1) was recently shown to promote β-cell survival during lipotoxic stress. Here we show that ER-localized THBS1 is cytoprotective to rat, mouse, and human β-cells exposed to cytokines or thapsigargin-induced ER stress. THBS1 confers cytoprotection by maintaining expression of mesencephalic astrocyte-derived neutrotrophic factor (MANF) in β-cells and thereby prevents the BH3-only protein BIM (BCL2-interacting mediator of cell death)-dependent triggering of the mitochondrial pathway of apoptosis. Prolonged exposure of β-cells to cytokines or thapsigargin leads to THBS1 and MANF degradation and loss of this prosurvival mechanism. Approaches that sustain intracellular THBS1 and MANF expression in β-cells should be explored as a cytoprotective strategy in type 1 diabetes.

KEYWORDS:

IL-1; cytokine; endoplasmic reticulum stress (ER stress); inflammation; interferon; islet; mitochondrial apoptosis; thrombospondin; type 1 diabetes; β-cell

PMID:
28698383
PMCID:
PMC5592674
DOI:
10.1074/jbc.M116.769877
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center