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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / metabolism
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Inflammation / metabolism*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Mice
  • Nerve Growth Factors / antagonists & inhibitors
  • Nerve Growth Factors / metabolism*
  • Oxidative Stress
  • Thapsigargin / pharmacology
  • Thrombospondin 1 / metabolism*


  • Cytokines
  • MANF protein, human
  • MANF protein, mouse
  • Nerve Growth Factors
  • Thrombospondin 1
  • Thapsigargin