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

par Andrade Da Cunha, Daniel ;Cito, Monia ;Grieco, Fabio Arturo ;Cosentino, Cristina ;Danilova, Tatiana;Ladrière, Laurence ;Lindahl, Maria;Domanskyi, Andrii;Bugliani, Marco;Marchetti, Piero;Eizirik, Decio L. ;Cnop, Miriam
Référence The Journal of biological chemistry, 292, 36, page (14977-14988)
Publication Publié, 2017

Article révisé par les pairs

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Résumé :

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, andhumanβ-cells exposed to cytokines or thapsigargininduced 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 ofβ-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.