RIG-I-driven CDKN1A stabilization reinforces cellular senescence

Cui Wang^#^{1

2

3}, Xiaoyu Jiang^#^{4

3}, Hong-Yu Li^#^{5

3}, Jianli Hu^{1

2

3}, Qianzhao Ji^{4

3}, Qiaoran Wang^{1

2

3}, Xiaoqian Liu^{4

6}, Daoyuan Huang^{7

8}, Kaowen Yan^{4

6}, Liyun Zhao^{7

8}, Yanling Fan^{1

2}, Si Wang^{7

8

9}, Shuai Ma^{4

9}, Juan Carlos Izpisua Belmonte¹⁰, Jing Qu^{11

12

13

14}, Guang-Hui Liu^{15

16

17

18

19

20}, Weiqi Zhang^{21

22

23

24}

Affiliations

¹ China National Center for Bioinformation, Beijing, 100101, China.
² Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
³ University of Chinese Academy of Sciences, Beijing, 100049, China.
⁴ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
⁵ Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
⁶ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
⁷ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
⁸ Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
⁹ Aging Biomarker Consortium, Beijing, 100101, China.
¹⁰ Altos Labs, Inc., San Diego, CA, 94022, USA.
¹¹ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. qujing@ioz.ac.cn.
¹² University of Chinese Academy of Sciences, Beijing, 100049, China. qujing@ioz.ac.cn.
¹³ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China. qujing@ioz.ac.cn.
¹⁴ Aging Biomarker Consortium, Beijing, 100101, China. qujing@ioz.ac.cn.
¹⁵ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. ghliu@ioz.ac.cn.
¹⁶ University of Chinese Academy of Sciences, Beijing, 100049, China. ghliu@ioz.ac.cn.
¹⁷ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China. ghliu@ioz.ac.cn.
¹⁸ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China. ghliu@ioz.ac.cn.
¹⁹ Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, 100053, China. ghliu@ioz.ac.cn.
²⁰ Aging Biomarker Consortium, Beijing, 100101, China. ghliu@ioz.ac.cn.
²¹ China National Center for Bioinformation, Beijing, 100101, China. zhangwq@big.ac.cn.
²² Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. zhangwq@big.ac.cn.
²³ University of Chinese Academy of Sciences, Beijing, 100049, China. zhangwq@big.ac.cn.
²⁴ Aging Biomarker Consortium, Beijing, 100101, China. zhangwq@big.ac.cn.

^# Contributed equally.

PMID: 40133712
DOI: 10.1007/s11427-024-2844-8

RIG-I-driven CDKN1A stabilization reinforces cellular senescence

Cui Wang et al. Sci China Life Sci. 2025 Jun.

. 2025 Jun;68(6):1646-1661.

doi: 10.1007/s11427-024-2844-8. Epub 2025 Mar 24.

Authors

Affiliations

¹ China National Center for Bioinformation, Beijing, 100101, China.
² Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
³ University of Chinese Academy of Sciences, Beijing, 100049, China.
⁴ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
⁵ Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
⁶ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
⁷ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
⁸ Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
⁹ Aging Biomarker Consortium, Beijing, 100101, China.
¹⁰ Altos Labs, Inc., San Diego, CA, 94022, USA.
¹¹ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. qujing@ioz.ac.cn.
¹² University of Chinese Academy of Sciences, Beijing, 100049, China. qujing@ioz.ac.cn.
¹³ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China. qujing@ioz.ac.cn.
¹⁴ Aging Biomarker Consortium, Beijing, 100101, China. qujing@ioz.ac.cn.
¹⁵ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. ghliu@ioz.ac.cn.
¹⁶ University of Chinese Academy of Sciences, Beijing, 100049, China. ghliu@ioz.ac.cn.
¹⁷ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China. ghliu@ioz.ac.cn.
¹⁸ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China. ghliu@ioz.ac.cn.
¹⁹ Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing, 100053, China. ghliu@ioz.ac.cn.
²⁰ Aging Biomarker Consortium, Beijing, 100101, China. ghliu@ioz.ac.cn.
²¹ China National Center for Bioinformation, Beijing, 100101, China. zhangwq@big.ac.cn.
²² Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. zhangwq@big.ac.cn.
²³ University of Chinese Academy of Sciences, Beijing, 100049, China. zhangwq@big.ac.cn.
²⁴ Aging Biomarker Consortium, Beijing, 100101, China. zhangwq@big.ac.cn.

^# Contributed equally.

PMID: 40133712
DOI: 10.1007/s11427-024-2844-8

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^Cip1 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.

Keywords: RIG-I; aging; human stem cell; innate immune pathway; senescence.

PubMed Disclaimer

Conflict of interest statement

Compliance and ethics. The authors declare that they have no conflict of interest.

References

1. Aging Atlas Consortium, et al. (2021). Aging Atlas: a multi-omics database for aging biology. Nucleic Acids Res 49, D825–D830. - DOI
1. Aging Biomarker Consortium, Bao, H., Cao, J., Chen, M., Chen, M., Chen, W., Chen, X., Chen, Y., Chen, Y., Chen, Y., Chen, Z., et al. (2023). Biomarkers of aging. Sci China Life Sci 66, 893–1066. - PMC - DOI
1. Asdonk, T., Motz, I., Werner, N., Coch, C., Barchet, W., Hartmann, G., Nickenig, G., and Zimmer, S. (2012). Endothelial RIG-I activation impairs endothelial function. Biochem Biophys Res Commun 420, 66–71. - PubMed - DOI
1. Bi, S., Liu, Z., Wu, Z., Wang, Z., Liu, X., Wang, S., Ren, J., Yao, Y., Zhang, W., Song, M., et al. (2020). SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer. Protein Cell 11, 483–504. - PubMed - PMC - DOI
1. Cai, Y., Song, W., Li, J., Jing, Y., Liang, C., Zhang, L., Zhang, X., Zhang, W., Liu, B., An, Y., et al. (2022). The landscape of aging. Sci China Life Sci 65, 2354–2454. - PubMed - PMC - DOI

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Springer

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

RIG-I-driven CDKN1A stabilization reinforces cellular senescence

Affiliations

RIG-I-driven CDKN1A stabilization reinforces cellular senescence

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

LinkOut - more resources

Full Text Sources