p85α deficiency protects β-cells from endoplasmic reticulum stress-induced apoptosis
p85α deficiency protects β-cells from endoplasmic reticulum stress-induced apoptosis
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DOI：
10.1073/pnas.1322564111
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发表时间：
2014-01-21
影响因子：
11.1
通讯作者：
Kahn, C. Ronald
中科院分区：
文献类型：
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作者：
Winnay, Jonathon N.;Dirice, Ercument;Kahn, C. Ronald
在 2 型糖尿病等胰岛素抵抗状态下，β 细胞合成和分泌胰岛素的需求很高，这对内质网 (ER) 合成和折叠新生蛋白质的能力提出了挑战。这会产生一种内质网应激状态，触发称为未折叠蛋白反应（UPR）的协调程序，试图恢复内质网稳态。我们确定了 PI3K 的 p85 α 调节亚基通过促进 X-box 结合蛋白 1（UPR 的核心转录因子）的核定位来调节 UPR 的作用。在本研究中，我们证明减少β细胞中p85a的表达可以显着延迟在表达突变胰岛素分子的Akita(+/-)小鼠中观察到的糖尿病表型的发作和严重程度。这是由于内质网应激依赖性细胞凋亡途径的激活减少以及β细胞质量和功能的保留。这些数据表明，p85 α 的调节可以保护胰腺 β 细胞免受 ER 应激，指出糖尿病状态下的潜在治疗靶点。
In insulin resistant states such as type 2 diabetes, there is a high demand on the beta-cell to synthesize and secrete insulin, which challenges the ability of the endoplasmic reticulum (ER) to synthesize and fold nascent proteins. This creates a state of ER stress that triggers a coordinated program referred to as the unfolded protein response (UPR) that attempts to restore ER homeostasis. We identified a role for the p85 alpha regulatory subunit of PI3K to modulate the UPR by promoting the nuclear localization of X-box binding protein 1, a transcription factor central to the UPR. In the present study we demonstrate that reducing p85a expression in beta-cells can markedly delay the onset and severity of the diabetic phenotype observed in Akita(+/-) mice, which express a mutant insulin molecule. This is due to a decrease in activation of ER stress-dependent apoptotic pathways and a preservation of beta-cell mass and function. These data demonstrate that modulation of p85 alpha can protect pancreatic beta-cells from ER stress, pointing to a potentially therapeutic target in diabetic states.