RESUMO
In pancreatic beta cells, the endoplasmic reticulum (ER) is an important site for insulin biosynthesis and the folding of newly synthesized proinsulin. Here, we show that IRE1alpha, an ER-resident protein kinase, has a crucial function in insulin biosynthesis. IRE1alpha phosphorylation is coupled to insulin biosynthesis in response to transient exposure to high glucose; inactivation of IRE1alpha signaling by siRNA or inhibition of IRE1alpha phosphorylation hinders insulin biosynthesis. IRE1 activation by high glucose does not accompany XBP-1 splicing and BiP dissociation but upregulates its target genes such as WFS1. Thus, IRE1 signaling activated by transient exposure to high glucose uses a unique subset of downstream components and has a beneficial effect on pancreatic beta cells. In contrast, chronic exposure of beta cells to high glucose causes ER stress and hyperactivation of IRE1, leading to the suppression of insulin gene expression. IRE1 signaling is therefore a potential target for therapeutic regulation of insulin biosynthesis.
Assuntos
Retículo Endoplasmático/metabolismo , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/biossíntese , Proteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo/genética , Chaperona BiP do Retículo Endoplasmático , Regulação da Expressão Gênica/fisiologia , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Hiperglicemia/metabolismo , Hiperglicemia/fisiopatologia , Insulina/metabolismo , Secreção de Insulina , Proteínas de Membrana/genética , Camundongos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosforilação , Proinsulina/metabolismo , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Ratos , Fatores de Transcrição de Fator Regulador X , Transdução de Sinais/fisiologia , Estresse Fisiológico/metabolismo , Estresse Fisiológico/fisiopatologia , Fatores de Transcrição , Regulação para Cima/fisiologia , Proteína 1 de Ligação a X-BoxRESUMO
In Wolfram syndrome, a rare form of juvenile diabetes, pancreatic beta-cell death is not accompanied by an autoimmune response. Although it has been reported that mutations in the WFS1 gene are responsible for the development of this syndrome, the precise molecular mechanisms underlying beta-cell death caused by the WFS1 mutations remain unknown. Here we report that WFS1 is a novel component of the unfolded protein response and has an important function in maintaining homeostasis of the endoplasmic reticulum (ER) in pancreatic beta-cells. WFS1 encodes a transmembrane glyco-protein in the ER. WFS1 mRNA and protein are induced by ER stress. The expression of WFS1 is regulated by inositol requiring 1 and PKR-like ER kinase, central regulators of the unfolded protein response. WFS1 is normally up-regulated during insulin secretion, whereas inactivation of WFS1 in beta-cells causes ER stress and beta-cell dysfunction. These results indicate that the pathogenesis of Wolfram syndrome involves chronic ER stress in pancreatic beta-cells caused by the loss of function of WFS1.
Assuntos
Retículo Endoplasmático/fisiologia , Células Secretoras de Insulina/fisiologia , Proteínas de Membrana/fisiologia , Animais , Células COS , Linhagem Celular , Chlorocebus aethiops , Endorribonucleases , Homeostase , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Modelos Biológicos , Mutação , Dobramento de Proteína , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais , Síndrome de Wolfram/etiologiaRESUMO
Endoplasmic reticulum (ER) stress, which is caused by the accumulation of misfolded proteins in the ER, elicits an adaptive response, the unfolded protein response (UPR). One component of the UPR, the endoplasmic reticulum-associated protein degradation (ERAD) system, has an important function in the survival of ER stressed cells. Here, we show that HRD1, a component of the ERAD system, is upregulated in pancreatic islets of the Akita diabetes mouse model and enhances intracellular degradation of misfolded insulin. High ER stress in beta-cells stimulated mutant insulin degradation through HRD1 to protect beta-cells from ER stress and ensuing death. If HRD1 serves the same function in humans, it may serve as a target for therapeutic intervention in diabetes.
