由IRE1β介导的未折叠蛋白质反应被粘素生产细胞中的伴侣AGR2抑制
Lisa Neidhardt1, Eva Cloots2,3, Natalie Friemel4
1Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK. ln327@cam.ac.uk.
The EMBO journal
|January 4, 2024
概括
杯状细胞使用一种特殊的未折叠蛋白反应 (UPR) 途径,涉及IRE1β和AGR2. 这种系统积极抑制IRE1β活动,将其与一般的UPR传感器不同,将其与粘素生产的挑战联系起来.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 蛋白质稳定性 蛋白质稳定性
背景情况:
- 展开的蛋白质反应 (UPR) 维持了内细胞网膜 (ER) 的蛋白质稳定.
- 已知UPR的效应机制,但感知通路的理解较少.
- 玻璃杯细胞拥有专门的ER,具有独特的蛋白质静止需求.
研究的目的:
- 为了研究杯状细胞中UPR的传感机制.
- 确定IRE1β和AGR2在调节乳腺蛋白质稳定在产生粘素的细胞中的作用.
- 为了区分杯状细胞中的专门的UPR与一般的UPR通路.
主要方法:
- 使用的中国仓鼠卵巢 (CHO) 细胞被设计成表达 IRE1β/α 嵌合体.
- 研究了粘素特异性护师AGR2对IRE1活性的影响.
- 引入了杯状细胞特异性客户端MUC2,以评估其对镇压的影响.
- 进行了体外测试,以分析AGR2与IRE1β光域之间的相互作用.
主要成果:
- 将 IRE1α 的光域替换为 IRE1β 的调节后的基底 IRE1 活动.
- AGR2抑制了 IRE1β/α 嵌合体活动,但不是本地 IRE1α.
- 引入MUC2逆转了IRE1β/α仿真体的AGR2介导的抑制.
- 在实验室中,AGR2破坏了IRE1β二聚体的稳定,并与单聚体形成复合物.
结论:
- 在杯状细胞中,AGR2 活跃抑制 IRE1β 活动.
- 这种压抑使IRE1活动受制于细胞特异性蛋白静态挑战.
- IRE1β-AGR2系统代表了一个专门的UPR机制,与一般的UPR传感器不同.
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