逐渐的ER耗尽会导致渐进且可逆的UPR信号
Ilaria Pontisso1, Roberto Ornelas-Guevara2, Eric Chevet3,4
1U1282 "Calcium Signaling and Microbial Infections", Institut de Biologie Intégrative de la Cellule (I2BC)-Université Paris-Saclay, Gif-Sur-Yvette 91190, France.
PNAS nexus
|June 27, 2024
概括
展开的蛋白质反应 (UPR) 是由内质网膜 (ER) 水平动态调节的. 这项研究揭示了一种剂量敏感的,依赖于Ca2+的循环,控制UPR的激活和失活,影响细胞命运.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 展开的蛋白质反应 (UPR) 是一个由内质网膜 (ER) 应激激活的关键细胞通路.
- 细胞内网膜 (ER) (Ca2+) 稳态对于细胞功能至关重要,其破坏是一个强大的UPR诱导剂.
- 在ER Ca2+水平和UPR激活动力学之间确切的关系仍然不完全理解.
研究的目的:
- 为了研究三个UPR传感器 (IRE1α,PERK,ATF6α) 激活响应受控ER Ca2+变化的灵敏度和时间依赖性.
- 阐明ER Ca2+波动与UPR信号之间的动态相互作用.
- 了解UPR激活和关闭的可塑性.
主要方法:
- 在人类培养细胞中利用了Ca2+成像,光漂白后的光恢复,生物化学分析和数学建模.
- 控制ER Ca2+度以诱导不同程度的ER压力.
- 监测了IRE1α,PERK和ATF6α的激活动态.
主要成果:
- 发现了 IRE1α UPR 分支的非线性激活率.
- 观察到PERK和ATF6α UPR分支的逐渐激活,需要更显著的ER Ca2+耗尽.
- 证明所有三个UPR臂在1小时内激活,并且在ER Ca2+补充后迅速 (<15分钟) 发生停用,突出显示UPR可塑性.
结论:
- UPR激活是一个动态的,对剂量敏感的过程,受到ER Ca2+水平的严格调节.
- UPR传感器的Ca2+依赖的激活/关闭循环提供了一种控制压力下细胞命运的机制.
- 这种可塑性使细胞能够迅速应对并从ER压力中恢复,从而影响生存和适应.
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