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Inhibition of the PI 3‐kinase pathway disrupts the unfolded protein response and reduces sensitivity to ER stress‐dependent apoptosis
The FASEB Journal ( IF 4.4 ) Pub Date : 2020-08-03 , DOI: 10.1096/fj.202000892r
Jonathon N Winnay 1 , Marie H Solheim 1, 2 , Masaji Sakaguchi 1, 3 , Pål R Njølstad 2, 4 , C Ronald Kahn 1
Affiliation  

Class Ia phosphoinositide 3‐kinases (PI3K) are critical mediators of insulin and growth factor action. We have demonstrated that the p85α regulatory subunit of PI3K modulates the unfolded protein response (UPR) by interacting with and regulating the nuclear translocation of XBP‐1s, a transcription factor essential for the UPR. We now show that PI3K activity is required for full activation of the UPR. Pharmacological inhibition of PI3K in cells blunts the ER stress‐dependent phosphorylation of IRE1α and PERK, decreases induction of ATF4, CHOP, and XBP‐1 and upregulates UPR target genes. Cells expressing a human p85α mutant (R649W) previously shown to inhibit PI3K, exhibit decreased activation of IRE1α and PERK and reduced induction of CHOP and ATF4. Pharmacological inhibition of PI3K, overexpression of a mutant of p85α that lacks the ability to interact with the p110α catalytic subunit (∆p85α) or expression of mutant p85α (R649W) in vivo, decreased UPR‐dependent induction of ER stress response genes. Acute tunicamycin treatment of R649W+/− mice revealed reduced induction of UPR target genes in adipose tissue, whereas chronic tunicamycin exposure caused sustained increases in UPR target genes in adipose tissue. Finally, R649W+/− cells exhibited a dramatic resistance to ER stress‐dependent apoptosis. These data suggest that PI3K pathway dysfunction causes ER stress that may drive the pathogenesis of several diseases including Type 2 diabetes and various cancers.

中文翻译:

抑制 PI 3-激酶途径会破坏未折叠蛋白反应并降低对 ER 应激依赖性细胞凋亡的敏感性

Ia 类磷酸肌醇 3-激酶 (PI3K) 是胰岛素和生长因子作用的关键介质。我们已经证明 PI3K 的 p85α 调节亚基通过与 XBP-1s 的核易位相互作用和调节未折叠蛋白反应 (UPR),XBP-1s 是 UPR 必不可少的转录因子。我们现在表明,完全激活 UPR 需要 PI3K 活动。细胞中 PI3K 的药理抑制作用会减弱 IRE1α 和 PERK 的 ER 应激依赖性磷酸化,减少 ATF4、CHOP 和 XBP-1 的诱导并上调 UPR 靶基因。表达人类 p85α 突变体 (R649W) 的细胞先前显示可抑制 PI3K,表现出 IRE1α 和 PERK 的激活减少以及 CHOP 和 ATF4 的诱导减少。PI3K的药理抑制作用,缺乏与 p110α 催化亚基 (Δp85α) 相互作用的能力的 p85α 突变体的过表达或突变体 p85α (R649W) 在体内的表达降低了 ER 应激反应基因的 UPR 依赖性诱导。R649W+/- 小鼠的急性衣霉素治疗显示脂肪组织中 UPR 靶基因的诱导减少,而慢性衣霉素暴露导致脂肪组织中 UPR 靶基因的持续增加。最后,R649W++/- 细胞对 ER 应激依赖性细胞凋亡表现出显着的抵抗力。这些数据表明 PI3K 通路功能障碍会导致 ER 应激,从而可能导致包括 2 型糖尿病和各种癌症在内的多种疾病的发病机制。R649W+/- 小鼠的急性衣霉素治疗显示脂肪组织中 UPR 靶基因的诱导减少,而慢性衣霉素暴露导致脂肪组织中 UPR 靶基因的持续增加。最后,R649W++/- 细胞对 ER 应激依赖性细胞凋亡表现出显着的抵抗力。这些数据表明 PI3K 通路功能障碍会导致 ER 应激,从而可能导致包括 2 型糖尿病和各种癌症在内的多种疾病的发病机制。R649W+/- 小鼠的急性衣霉素治疗显示脂肪组织中 UPR 靶基因的诱导减少,而慢性衣霉素暴露导致脂肪组织中 UPR 靶基因的持续增加。最后,R649W++/- 细胞对 ER 应激依赖性细胞凋亡表现出显着的抵抗力。这些数据表明 PI3K 通路功能障碍会导致 ER 应激,从而可能导致包括 2 型糖尿病和各种癌症在内的多种疾病的发病机制。
更新日期:2020-08-03
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