Pancreatic ß-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, 2017 09 08.
Article
em En
| MEDLINE
| ID: mdl-28698383
ABSTRACT
Cytokine-induced endoplasmic reticulum (ER) stress is one of the molecular mechanisms underlying pancreatic ß-cell demise in type 1 diabetes. Thrombospondin 1 (THBS1) was recently shown to promote ß-cell survival during lipotoxic stress. Here we show that ER-localized THBS1 is cytoprotective to rat, mouse, and human ß-cells exposed to cytokines or thapsigargin-induced ER stress. THBS1 confers cytoprotection by maintaining expression of mesencephalic astrocyte-derived neutrotrophic factor (MANF) in ß-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 ß-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 ß-cells should be explored as a cytoprotective strategy in type 1 diabetes.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Trombospondina 1
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Células Secretoras de Insulina
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Inflamação
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Fatores de Crescimento Neural
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Bélgica