IRF3激活RB以授权cGAS-STING诱导的衰老和减轻肝纤维化
Qirou Wu1, Xiaohong Leng1, Qian Zhang1,2
1MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
Science advances
|February 28, 2024
概括
通过cGAS-STING传感细胞核DNA,激活干扰素调节因子3 (IRF3),该因子与视网膜母细胞瘤 (RB) 结合,诱导细胞衰老并限制肝纤维化.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- 通过循环GMP-AMP合成酶 (cGAS) -干扰基因刺激器 (STING) 途径感知细胞质DNA,启动先天免疫反应和细胞衰老.
- 确切的机制和STING诱导的衰老的生理意义仍然不完全理解.
研究的目的:
- 为了阐明底层STING介导的细胞衰老的详细机制.
- 研究STING-IRF3-RB信号在肝纤维化中的生理作用.
主要方法:
- 研究了干扰素调节因子3 (IRF3) 和核中的视网膜母细胞瘤 (RB) 之间的相互作用.
- 使用了具有全球IRF3淘汰或肝星细胞 (HSCs) 条件删除的小鼠模型.
- 评估了CDK4/6抑制对肝纤维化的影响.
主要成果:
- 干扰素调节因子3 (IRF3) 与视网膜母细胞瘤 (RB) 形成核复合体,视网膜母细胞瘤 (RB) 是细胞循环的关键调节器.
- 这种相互作用抑制了循环素依赖激酶4/6 (CDK4/6) 介导的RB过酸化,防止E2F转录因子的失活,促进衰老.
- STING-IRF3-RB信号诱导激活的肝星细胞 (HSC) 衰老,缓解肝纤维化进展.
- 缺少IRF3会加剧肝纤维化,而CDK4/6抑制剂可以缓解肝纤维化.
结论:
- 一个新的机制揭示了cGAS-STING信号如何通过IRF3-RB相互作用诱导细胞衰老.
- 这一途径通过促进HSC衰老,在限制肝纤维化方面发挥着关键作用.
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