| First Author | Cunha DA | Year | 2017 |
| Journal | J Biol Chem | Volume | 292 |
| Issue | 36 | Pages | 14977-14988 |
| PubMed ID | 28698383 | Mgi Jnum | J:245893 |
| Mgi Id | MGI:5915677 | Doi | 10.1074/jbc.M116.769877 |
| Citation | Cunha DA, et al. (2017) Pancreatic beta-cell protection from inflammatory stress by the endoplasmic reticulum proteins thrombospondin 1 and mesencephalic astrocyte-derived neutrotrophic factor (MANF). J Biol Chem 292(36):14977-14988 |
| abstractText | Cytokine-induced endoplasmic reticulum (ER) stress is one of the molecular mechanisms underlying pancreatic beta-cell demise in type 1 diabetes. Thrombospondin 1 (THBS1) was recently shown to promote beta-cell survival during lipotoxic stress. Here we show that ER-localized THBS1 is cytoprotective to rat, mouse, and human beta-cells exposed to cytokines or thapsigargin-induced ER stress. THBS1 confers cytoprotection by maintaining expression of mesencephalic astrocyte-derived neutrotrophic factor (MANF) in beta-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 beta-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 beta-cells should be explored as a cytoprotective strategy in type 1 diabetes. |
