对IRE1α RNase的Allosteric抑制可以在内分泌网膜应激过程中保持细胞活力和功能
Rajarshi Ghosh1, Likun Wang2, Eric S Wang3
1Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Lung Biology Center, University of California, San Francisco, San Francisco, CA 94143, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell
|July 15, 2014
概括
称为KIRAs的小分子可以抑制IRE1α,这是一种参与细胞内网膜 (ER) 应激的蛋白质. 这种抑制促进细胞存活,并保护各种组织免受ER压力相关的退化.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 生物化学 生物化学
背景情况:
- 细胞内膜网膜 (ER) 应激反应涉及蛋白质IRE1α,它决定了适应和亡之间的细胞命运.
- IRE1α激活涉及 homo-oligomerization 和自酸化,导致 XBP1 mRNA 拼接以进行适应.
- 在严重的ER压力下,IRE1α的扩展活性通过分裂额外的mRNA促进了细胞亡.
研究的目的:
- 通过抑制其RNase功能来调节IRE1α活性的小分子的开发.
- 在ER压力相关疾病的临床前模型中研究这些抑制剂的治疗潜力.
主要方法:
- 设计和合成具有ATP竞争力的IRE1α激酶抑制RNase减弱剂 (KIRAs).
- 在试验室和体内对KIRA在抑制IRE1α方面的疗效进行了评估.
- 在视网膜退化和阿基塔糖尿病小鼠的老鼠模型中评估KIRA6.
主要成果:
- KIRAs被开发用于通过破坏寡合体来全质抑制IRE1α.
- 优化的KIRA6在体内证明了IRE1α的抑制,并在ER压力下促进了细胞存活.
- 在视网膜退化模型中,KIRA6保留了光受体活力,在糖尿病小鼠中保护了胰腺β细胞.
结论:
- 在ER压力期间,IRE1α活性是细胞命运的关键决定因素.
- 像KIRA6这样的小分子抑制剂提供了一种潜在的治疗策略,以减轻ER压力诱导的细胞退化.
- 用KIRA针对IRE1α显示出治疗视网膜退化和糖尿病等疾病的前景.
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