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<p>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 <i>CDKN1A</i> mRNA being a prominent target. Specifically, RIG-I stabilizes <i>CDKN1A</i> mRNA, resulting in elevated <i>CDKN1A</i> transcript levels and increased p21<sup>Cip1</sup> 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.</p>

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RIG-I-driven CDKN1A stabilization reinforces cellular senescence

  • 期刊论文

  • 发表日期：

    2025年3月24日

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  • Cui Wang,
  • Xiaoyu Jiang,
  • Hong-Yu Li,
  • Jianli Hu,
  • Qianzhao Ji,
  • Qiaoran Wang,
  • Xiaoqian Liu,
  • Daoyuan Huang,
  • Kaowen Yan,
  • Liyun Zhao,
  • Yanling Fan,
  • Si Wang,
  • Shuai Ma,
  • Juan Carlos Izpisua Belmonte,
  • Jing Qu,
  • Guang-Hui Liu,
  • Weiqi Zhang

摘要

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 p21Cip1 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.