RIG-I-driven CDKN1A stabilization reinforces cellular senescence.

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

China National Center for Bioinformation, Beijing, 100101, China. · pubmed

Paper

Abstract

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

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Research summary

RIG-I stabilization of CDKN1A mRNA drives cellular senescence in human mesenchymal stem cells. This study explores the mechanistic link between innate immune signaling and cellular aging, addressing a potential root cause of aging through the modulation of senescence pathways.

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