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The IRE1?/XBP1s Pathway Is Essential for the Glucose Response and Protection of ? Cells.

ABSTRACT: Although glucose uniquely stimulates proinsulin biosynthesis in ? cells, surprisingly little is known of the underlying mechanism(s). Here, we demonstrate that glucose activates the unfolded protein response transducer inositol-requiring enzyme 1 alpha (IRE1?) to initiate X-box-binding protein 1 (Xbp1) mRNA splicing in adult primary ? cells. Using mRNA sequencing (mRNA-Seq), we show that unconventional Xbp1 mRNA splicing is required to increase and decrease the expression of several hundred mRNAs encoding functions that expand the protein secretory capacity for increased insulin production and protect from oxidative damage, respectively. At 2 wk after tamoxifen-mediated Ire1? deletion, mice develop hyperglycemia and hypoinsulinemia, due to defective ? cell function that was exacerbated upon feeding and glucose stimulation. Although previous reports suggest IRE1? degrades insulin mRNAs, Ire1? deletion did not alter insulin mRNA expression either in the presence or absence of glucose stimulation. Instead, ? cell failure upon Ire1? deletion was primarily due to reduced proinsulin mRNA translation primarily because of defective glucose-stimulated induction of a dozen genes required for the signal recognition particle (SRP), SRP receptors, the translocon, the signal peptidase complex, and over 100 other genes with many other intracellular functions. In contrast, Ire1? deletion in ? cells increased the expression of over 300 mRNAs encoding functions that cause inflammation and oxidative stress, yet only a few of these accumulated during high glucose. Antioxidant treatment significantly reduced glucose intolerance and markers of inflammation and oxidative stress in mice with ? cell-specific Ire1? deletion. The results demonstrate that glucose activates IRE1?-mediated Xbp1 splicing to expand the secretory capacity of the ? cell for increased proinsulin synthesis and to limit oxidative stress that leads to ? cell failure.

SUBMITTER: Hassler JR

PROVIDER: S-EPMC4607427 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells.

Hassler Justin R JR Scheuner Donalyn L DL Wang Shiyu S Han Jaeseok J Kodali Vamsi K VK Li Philip P Nguyen Julie J George Jenny S JS Davis Cory C Wu Shengyang P SP Bai Yongsheng Y Sartor Maureen M Cavalcoli James J Malhi Harmeet H Baudouin Gregory G Zhang Yaoyang Y Yates John R JR Itkin-Ansari Pamela P Volkmann Niels N Kaufman Randal J RJ

PLoS biology 20151015 10

Although glucose uniquely stimulates proinsulin biosynthesis in β cells, surprisingly little is known of the underlying mechanism(s). Here, we demonstrate that glucose activates the unfolded protein response transducer inositol-requiring enzyme 1 alpha (IRE1α) to initiate X-box-binding protein 1 (Xbp1) mRNA splicing in adult primary β cells. Using mRNA sequencing (mRNA-Seq), we show that unconventional Xbp1 mRNA splicing is required to increase and decrease the expression of several hundred mRNA ...[more]

PMID: 26469762

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Project description:Energy sensing is indispensable to balance anabolic and catabolic processes for the maintenance of cell viability. Pancreatic β cells are especially relevant because of their involvement in the coordination of insulin secretion when glucose concentration arises in the local milieu. In this work, we uncover the increased susceptibility of pancreatic β cells to cell death in response to different energy stressors. Upon glucose decline, from 25 to 5 mM, caused by stimulation with either 2-deoxyglucose or metformin, only pancreatic β cells showed an increase in cell death. Very interestingly, when we transfected either mouse insulinoma cell or human embryo kidney cells with a phospho-mutant form of B cell lymphoma 2 associated agonist of cell death at serine 155 (BAD S155D), an increase in the pro-survival factor B cell lymphoma 2 was detected in pancreatic β cells and not in human embryonic kidney cells in the presence of the energetic stressors. This data suggests that the protective capacity of this mutant form is only present in cells that present glucokinase. In contrast, upon hyperactivation of mechanistic target of rapamycin complex 1 signaling by knocking-down tuberous sclerosis complex protein, we observed increased susceptibility to cell death in response to energy stress in both pancreatic and non-pancreatic β cells. Therefore, mechanistic target of rapamycin complex 1 signaling presents a dual effect on cell viability. On the one hand, a chronic inhibition of mechanistic target of rapamycin complex 1 activity in response to the energy status is deleterious for pancreatic β cells, being attenuated by the overexpression of B cell lymphoma 2 associated agonist of cell death S155D. On the other hand, mechanistic target of rapamycin complex 1 hyperactivity provokes a susceptibility to energetic stress-induced cell death. Taken together, these results may open potential implications for the use of glucokinase activators or mechanistic target of rapamycin complex 1 modulators for the maintenance of pancreatic β cells for longer periods of time avoiding its loss in different pathologies such as type 2 diabetes mellitus.

Dataset Information

The IRE1?/XBP1s Pathway Is Essential for the Glucose Response and Protection of ? Cells.

Publications

The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells.

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