通过甲基酸盐增加细胞蛋白质的修饰,激活了未折叠蛋白质响应的基于内分泌网膜的传感器
Mingzhan Xue1, Zehra Irshad2, Naila Rabbani3
1Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University (HBKU), Qatar Foundation, P.O. Box 34110, Doha, Qatar.
Redox biology
|January 10, 2024
概括
高葡萄糖会增加甲基糖 (MG),激活未折叠蛋白质反应 (UPR). 通过glyoxalase 1 (Glo1) 降低MG水平可以防止UPR激活,为高血糖症提供潜在的治疗方法.
科学领域:
- 细胞生物学 细胞生物学
- 代谢健康 代谢健康
- 细胞内膜网膜应激压力
背景情况:
- 展开的蛋白质反应 (UPR) 是被错误折叠的蛋白质激活的,涉及到内分泌网膜传感器 IRE1α,PERK 和 ATF6.
- 代谢功能障碍可能导致蛋白质错误折叠和UPR激活,但机制尚未完全理解.
- 甲基醇 (MG) 是一种在代谢健康受损时增加的代谢物,它会改变细胞蛋白质.
研究的目的:
- 研究高葡萄糖和甲基酸盐 (MG) 增加对UPR传感器激活的影响 (IRE1α,PERK,ATF6).
- 为了确定调节MG水平是否会影响UPR激活.
- 探索MG对蛋白质的修饰及其在UPR激活中的作用.
主要方法:
- 人类大动脉内皮细胞和HMEC-1细胞在低葡萄糖和高葡萄糖条件下培养.
- 操纵了glyoxalase 1 (Glo1) 表达以改变细胞MG水平.
- 评估了UPR传感器的激活和下游基因表达 (伴随性,亡性,炎症性).
主要成果:
- 由高葡萄糖引起的MG增加激活了IRE1α,PERK和ATF6.
- 这种激活导致伴侣基因,亡基因和炎症基因的表达增加.
- 增强Glo1表达以降低MG水平可以防止UPR激活.
- 蛋白质的MG修饰,形成胺MG-H1,导致展开并准PDI和伴侣,挑战蛋白质稳定.
结论:
- 在高葡萄糖条件下,升高的甲基甘 (MG) 是未折叠蛋白反应 (UPR) 激活的关键驱动因素.
- 调节MG水平,例如通过增加glyoxalase 1 (Glo1) 活性,可以防止UPR激活.
- 使用Glo1诱导剂的药理降低MG,为高血糖和糖尿病中与UPR相关的细胞功能障碍提供了潜在的治疗策略.
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