Wang Cui, Jiang Xiaoyu, Li Hong-Yu, Hu Jianli, Ji Qianzhao, Wang Qiaoran, Liu Xiaoqian, Huang Daoyuan, Yan Kaowen, Zhao Liyun, Fan Yanling, Wang Si, Ma Shuai, Belmonte Juan Carlos Izpisua, Qu Jing, Liu Guang-Hui, Zhang Weiqi
China National Center for Bioinformation, Beijing, 100101, China.
Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
Sci China Life Sci. 2025 Mar 24. doi: 10.1007/s11427-024-2844-8.
The innate immune signaling network follows a canonical format for signal transmission. The innate immune pathway is crucial for defense against pathogens, yet its mechanistic crosstalk with aging processes remains largely unexplored. Retinoic acid-inducible gene-I (RIG-I), a key mediator of antiviral immunity within this pathway, has an enigmatic role in stem cell senescence. Our study reveals that RIG-I levels increase in human genetic and physiological cellular aging models, and its accumulation drives cellular senescence. Conversely, CRISPR/Cas9-mediated RIG-I deletion or pharmacological inhibition in human mesenchymal stem cells (hMSCs) confers resistance to senescence. Mechanistically, RIG-I binds to endogenous mRNAs, with CDKN1A mRNA being a prominent target. Specifically, RIG-I stabilizes CDKN1A mRNA, resulting in elevated CDKN1A transcript levels and increased p21 protein expression, which precipitates senescence. Collectively, our findings establish RIG-I as a post-transcriptional regulator of senescence and suggest potential targets for the mitigation of aging-related diseases.
先天性免疫信号网络遵循一种规范的信号传递形式。先天性免疫途径对于抵御病原体至关重要，但其与衰老过程的机制性相互作用在很大程度上仍未得到探索。视黄酸诱导基因-I（RIG-I）是该途径中抗病毒免疫的关键介质，在干细胞衰老中具有神秘作用。我们的研究表明，在人类遗传和生理细胞衰老模型中RIG-I水平升高，其积累驱动细胞衰老。相反，在人间充质干细胞（hMSCs）中，CRISPR/Cas9介导的RIG-I缺失或药物抑制赋予了对衰老的抗性。从机制上讲，RIG-I与内源性mRNA结合，CDKN1A mRNA是一个主要靶点。具体而言，RIG-I使CDKN1A mRNA稳定，导致CDKN1A转录水平升高和p21蛋白表达增加，从而引发衰老。总的来说，我们的研究结果确立了RIG-I作为衰老的转录后调节因子，并为减轻衰老相关疾病提出了潜在靶点。
