GSBS Student Publications

Student Author(s)

Rajarshi Ghosh

GSBS Program

Interdisciplinary Graduate Program

UMMS Affiliation

Program in Gene Function and Expression; Program in Molecular Medicine

Date

2-21-2008

Document Type

Article

Medical Subject Headings

Animals; Blood Glucose; Cells, Cultured; Endoribonucleases; Insulin; Insulin-Secreting Cells; Mice; Protein Folding; Protein-Serine-Threonine Kinases; RNA, Messenger; Rats; Signal Transduction

Disciplines

Biochemistry, Biophysics, and Structural Biology | Life Sciences | Medicine and Health Sciences

Abstract

BACKGROUND:The endoplasmic reticulum (ER) is a cellular compartment for the biosynthesis and folding of newly synthesized secretory proteins such as insulin. Perturbations to ER homeostasis cause ER stress and subsequently activate cell signaling pathways, collectively known as the Unfolded Protein Response (UPR). IRE1alpha is a central component of the UPR. In pancreatic beta-cells, IRE1alpha also functions in the regulation of insulin biosynthesis.

PRINCIPAL FINDINGS:Here we report that hyperactivation of IRE1alpha caused by chronic high glucose treatment or IRE1alpha overexpression leads to insulin mRNA degradation in pancreatic beta-cells. Inhibition of IRE1alpha signaling using its dominant negative form prevents insulin mRNA degradation. Islets from mice heterozygous for IRE1alpha retain expression of more insulin mRNA after chronic high glucose treatment than do their wild-type littermates.

CONCLUSIONS/SIGNIFICANCE: These results reveal a role of IRE1alpha in insulin mRNA expression under ER stress conditions caused by chronic high glucose. The rapid degradation of insulin mRNA could provide immediate relief for the ER and free up the translocation machinery. Thus, this mechanism would preserve ER homeostasis and help ensure that the insulin already inside the ER can be properly folded and secreted. This adaptation may be crucial for the maintenance of beta-cell homeostasis and may explain why the beta-cells of type 2 diabetic patients with chronic hyperglycemia stop producing insulin in the absence of apoptosis. This mechanism may also be involved in suppression of the autoimmune type 1 diabetes by reducing the amount of misfolded insulin, which could be a source of "neo-autoantigens."

Rights and Permissions

Citation: PLoS ONE. 2008 Feb 20;3(2):e1648. Link to article on publisher's site

DOI of Published Version

10.1371/journal.pone.0001648

Related Resources

Link to Article in PubMed

Journal Title

PLoS ONE

PubMed ID

18286202

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