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

ABSTRACT: Cytokine-induced endoplasmic reticulum (ER) stress is one of the molecular mechanisms underlying pancreatic ?-cell demise in type 1 diabetes. Thrombospondin 1 (THBS1) was recently shown to promote ?-cell survival during lipotoxic stress. Here we show that ER-localized THBS1 is cytoprotective to rat, mouse, and human ?-cells exposed to cytokines or thapsigargin-induced ER stress. THBS1 confers cytoprotection by maintaining expression of mesencephalic astrocyte-derived neutrotrophic factor (MANF) in ?-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 ?-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 ?-cells should be explored as a cytoprotective strategy in type 1 diabetes.

SUBMITTER: Cunha DA 

PROVIDER: S-EPMC5592674 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature