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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Inducible Nitric-oxide Synthase and Nitric Oxide Donor Decrease Insulin Receptor Substrate-2 Protein Expression by Promoting Proteasome-dependent Degradation in Pancreatic β-Cells
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Inducible Nitric-oxide Synthase and Nitric Oxide Donor Decrease Insulin Receptor Substrate-2 Protein Expression by Promoting Proteasome-dependent Degradation in Pancreatic β-Cells

机译：诱导型一氧化氮合酶和一氧化氮供体减少胰岛素受体底物2蛋白表达通过促进蛋白酶体依赖性降解胰腺β细胞。

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Insulin receptor substrate-2 (IRS-2) plays a critical role in the survival and function of pancreatic β-cells. Gene disruption of IRS-2 results in failure of the β-cell compensatory mechanism and diabetes. Nonetheless, the regulation of IRS-2 protein expression in β-cells remains largely unknown. Inducible nitric-oxide synthase (iNOS), a major mediator of inflammation, has been implicated in β-cell damage in type 1 and type 2 diabetes. The effects of iNOS on IRS-2 expression have not yet been investigated in β-cells. Here, we show that iNOS and NO donor decreased IRS-2 protein expression in INS-1/832 insulinoma cells and mouse islets, whereas IRS-2 mRNA levels were not altered. Interleukin-1β (IL-1β), alone or in combination with interferon-γ (IFN-γ), reduced IRS-2 protein expression in an iNOS-dependent manner without altering IRS-2 mRNA levels. Proteasome inhibitors, MG132 and lactacystin, blocked the NO donor-induced reduction in IRS-2 protein expression. Treatment with NO donor led to activation of glycogen synthase kinase-3β (GSK-3β) and c-Jun N-terminal kinase (JNK/SAPK) in β-cells. Inhibition of GSK-3β by pharmacological inhibitors or siRNA-mediated knockdown significantly prevented NO donor-induced reduction in IRS-2 expression in β-cells. In contrast, a JNK inhibitor, SP600125, did not effectively block reduced IRS-2 expression in NO donor-treated β-cells. These data indicate that iNOS-derived NO reduces IRS-2 expression by promoting protein degradation, at least in part, through a GSK-3β-dependent mechanism. Our findings suggest that iNOS-mediated decreased IRS-2 expresssion may contribute to the progression and/or exacerbation of β-cell failure in diabetes.
机译：胰岛素受体底物2（IRS-2）在胰腺β细胞的存活和功能中起关键作用。 IRS-2的基因破坏导致β细胞代偿机制失败和糖尿病。尽管如此，IRS-2蛋白在β细胞中的表达调控仍然未知。诱导型一氧化氮合酶（iNOS）是炎症的主要介体，与1型和2型糖尿病的β细胞损伤有关。 iNOS对IRS-2表达的影响尚未在β细胞中进行研究。在这里，我们显示iNOS和NO供体降低了INS-1 / 832胰岛素瘤细胞和小鼠胰岛中IRS-2蛋白的表达，而IRS-2 mRNA的水平没有改变。白介素-1β（IL-1β）单独使用或与干扰素-γ（IFN-γ）结合使用，以iNOS依赖性方式降低IRS-2蛋白的表达，而不会改变IRS-2 mRNA的水平。蛋白酶体抑制剂MG132和lacacycystin阻止NO供体诱导的IRS-2蛋白表达降低。 NO供体的治疗导致β细胞中糖原合酶激酶3β（GSK-3β）和c-Jun N端激酶（JNK / SAPK）活化。药理抑制剂或siRNA介导的敲除对GSK-3β的抑制作用可显着阻止NO供体诱导的β细胞IRS-2表达减少。相反，JNK抑制剂SP600125在NO供体治疗的β细胞中并未有效地阻止IRS-2表达的降低。这些数据表明，iNOS衍生的NO至少部分地通过GSK-3β依赖性机制促进蛋白质降解，从而降低IRS-2表达。我们的发现表明，iNOS介导的IRS-2表达降低可能有助于糖尿病患者β细胞衰竭的进展和/或加重。

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