Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1
Graduate School of Biomedical Sciences; Program in Gene Function and Expression; Department of Medicine, Diabetes Division
Medical Subject Headings
Animals; Cell Line; Cell Line, Tumor; Cell Survival; DNA-Binding Proteins; Down-Regulation; Endoplasmic Reticulum; Gene Expression Regulation; Glucose; Heat-Shock Proteins; Hyperglycemia; Insulin; Insulin-Secreting Cells; Membrane Proteins; Mice; Molecular Chaperones; Nuclear Proteins; Phosphorylation; Proinsulin; Protein-Serine-Threonine Kinases; RNA Interference; Rats; Signal Transduction; Stress; Up-Regulation
Life Sciences | Medicine and Health Sciences
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.
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Citation: Cell Metab. 2006 Sep;4(3):245-54. Link to article on publisher's site
Lipson, Kathryn L.; Fonseca, Sonya G.; Ishigaki, Shinsuke; Nguyen, Linh X.; Foss, Elizabeth; Bortell, Rita; Rossini, Aldo A.; and Urano, Fumihiko, "Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1" (2006). GSBS Student Publications. Paper 769.