title: Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion.
abstract: As a key regulator of the unfolded protein response, the transcription factor XBP1 activates genes in protein secretory pathways and is required for the development of certain secretory cells. To elucidate the function of XBP1 in pancreatic β-cells, we generated β-cell-specific XBP1 mutant mice. Xbp1(f/f);RIP-cre mice displayed modest hyperglycemia and glucose intolerance resulting from decreased insulin secretion from β-cells. Ablation of XBP1 markedly decreased the number of insulin granules in β-cells, impaired proinsulin processing, increased the serum proinsulin:insulin ratio, blunted glucose-stimulated insulin secretion, and inhibited cell proliferation. Notably, XBP1 deficiency not only compromised the endoplasmic reticulum stress response in β-cells but also caused constitutive hyperactivation of its upstream activator, IRE1α, which could degrade a subset of mRNAs encoding proinsulin-processing enzymes. Hence, the combined effects of XBP1 deficiency on the canonical unfolded protein response and its negative feedback activation of IRE1α caused β-cell dysfunction in XBP1 mutant mice. These results demonstrate that IRE1α has dual and opposing roles in β-cells, and that a precisely regulated feedback circuit involving IRE1α and its product XBP1s is required to achieve optimal insulin secretion and glucose control.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA. ahlee@hsph.harvard.edu
authors.forename: Ann-Hwee
authors.initials: AH
authors.lastname: Lee
authors.forename: Keely
authors.initials: K
authors.lastname: Heidtman
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004722:Endoribonucleases / Q000502:physiology*; D025461:Feedback, Physiological; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D011384:Proinsulin / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D007328:Insulin; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D011384:Proinsulin; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D005947:Glucose