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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dual and opposing roles of the unfolded protein response regulated by IRE1α and XBP1 in proinsulin processing and insulin secretion
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Dual and opposing roles of the unfolded protein response regulated by IRE1α and XBP1 in proinsulin processing and insulin secretion

机译：IRE1α和XBP1调控的未折叠蛋白应答在胰岛素原加工和胰岛素分泌中的双重和相对作用

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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 p-cells, we generated p-cell-specific XBP1 mutant mice. Xbp1~(f/f);RIP-cre mice displayed modest hyperglycemia and glucose intolerance resulting from decreased insulin secretion from p-cells. Ablation of XBP1 markedly decreased the number of insulin granules in p-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 p-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 p-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.
机译：转录因子XBP1作为展开的蛋白质反应的关键调节因子，可激活蛋白质分泌途径中的基因，是某些分泌细胞发育所必需的。为了阐明XBP1在胰腺p细胞中的功能，我们生成了p细胞特异性XBP1突变小鼠。 Xbp1〜（f / f）; RIP-cre小鼠表现出适度的高血糖和葡萄糖不耐受，这是由于p细胞胰岛素分泌减少所致。 XBP1的消融显着减少了p细胞中胰岛素颗粒的数量，损害了胰岛素原的加工，增加了血清胰岛素原：胰岛素的比例，使葡萄糖刺激的胰岛素分泌减弱，并抑制了细胞增殖。值得注意的是，XBP1缺乏症不仅损害了p细胞的内质网应激反应，而且还导致其上游活化剂IRE1α的组成型过度活化，这可能会降解编码胰岛素原加工酶的mRNA的一部分。因此，XBP1缺乏对经典的未折叠蛋白应答及其IRE1α的负反馈激活的综合影响导致XBP1突变小鼠的p细胞功能障碍。这些结果表明，IRE1α在β细胞中具有双重和相反的作用，并且需要一个涉及IRE1α及其产物XBP1s的精确调节的反馈电路，以实现最佳的胰岛素分泌和葡萄糖控制。

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