The balance between adaptive and apoptotic unfolded protein responses regulates β-cell death under ER stress conditions through XBP1, CHOP and JNK. (15th September 2015)

• Record Type: Journal Article
• Authors: Chan, Jeng Yie; Luzuriaga, Jude; Maxwell, Emma L.; West, Phillip K.; Bensellam, Mohammed; Laybutt, D. Ross
• Is Part Of: Molecular and cellular endocrinology. Volume 413(2015)
• Page Start: 189
• Page End: 201
• Publication Date: 2015-09-15
• Subjects: β-Cell -- Diabetes -- Endoplasmic reticulum stress -- Islets -- Unfolded protein response; ATF4 activating transcription factor 4 -- ATF6 activating transcription factor 6 -- CHOP C/EBP homologous protein -- Edem1 ER degradation-enhancing alpha-mannosidase-like 1 -- eIF2α eukaryotic translation initiation factor 2α -- ER endoplasmic reticulum -- ERAD ER-associated degradation -- Erp72 endoplasmic reticulum protein 72 -- Fkbp11 FK506 binding protein 11 -- Grp94 94 kDa glucose-regulated protein -- IFN-γ interferon-gamma -- IL-1β interleukin-1β -- IRE1 inositol requiring enzyme 1 -- JNK Jun N-terminal kinase -- NOD Nonobese diabetic -- Orp150 150 kDa oxygen-regulated protein -- p58 protein kinase inhibitor of 58 kDa -- PERK PKR-like ER kinase -- TNF-α tumour necrosis factor-alpha -- Xbp1 X-box binding protein 1; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2015.06.025
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR) have been implicated in β-cell death in type 1 and type 2 diabetes. However, the UPR is also a fundamental mechanism required for β-cell adaptation and survival. The mechanisms regulating the transition from adaptive to apoptotic UPR remain to be clarified. Here, we investigated the relationships between XBP1, CHOP and JNK in the transition from adaptive to apoptotic UPR and β-cell death in models of type 1 and type 2 diabetes. XBP1 inhibition potentiated cell death induced by pro-inflammatory cytokines or the saturated fatty acid palmitate in MIN6 β-cells. This response was prevented by CHOP inhibition. IRE1/XBP1 inhibition led to alterations in islets from diabetes-resistant ob/ob mice that resemble those found in diabetes, including increases in cell death and inflammation and antioxidant gene expression. Similarly, IRE1/XBP1 inhibition increased cell death in islets from NOD mice. On the other hand, JNK inhibition: 1) increased adaptive UPR and reduced cell death in islets from diabetic db/db mice, and 2) restored adaptive UPR while protecting against apoptotic UPR gene expression and β-cell death and dysfunction following cytokine exposure. These findings suggest that the balance between XBP1-mediated adaptive and CHOP-dependent apoptotic UPR is critically important for β-cell survival during ER stress. JNK activation regulates the transition from adaptive to apoptotic UPR, thus providing a mechanism for β-cell propensity to cell death rather than ER stress adaptation in type 1 and type 2 diabetes. Highlights: Balance between adaptive and apoptotic UPR regulates β-cell survival during ER stress. XBP1 inhibition potentiates cytokine- and palmitate-induced β-cell death. JNK regulates the transition from adaptive UPR to β-cell death in diabetes.