YIF1A activates mTORC1 signaling to promote cellular senescence

  • Cell Death Dis. 2026 Jun 23. doi: 10.1038/s41419-026-09034-z.
Xiaogang Zhang  #  1 ,  Luying Liu  #  2 ,  Mengdi Shang  #  3 ,  Bin Hu  #  4 ,  Shu Zhu  5 ,  Xi Wang  6 ,  Jieying Liu  2 ,  Yanchun Han  6 ,  Xiaodan Wei  6 ,  Qi Cao  7 ,  Fan Li  6 ,  Lijie Gao  8  9 ,  Jingyu Sun  8  9 ,  Jiaqi Yu  10 ,  Chentai Tan  10 ,  Menghua Dong  11 ,  Tie-Shan Tang  12  13  14 ,  Jiu-Qiang Wang  15  16  17
Affiliations
  • 1. School of Special Education and Rehabilitation, Shandong Medical and Pharmaceutical University, Yantai, China.
  • 2. School of Life Sciences and Health, University of Health and Rehabilitation Sciences, Qingdao, China.
  • 3. Peninsular Cancer Center, Shandong Medical and Pharmaceutical University, Yantai, China.
  • 4. The First School of Clinical Medicine, Shandong Medical and Pharmaceutical University, Binzhou, China.
  • 5. Institute of Science and Technology Planning and Foresight, Chinese Academy of Science and Technology for Development, Beijing, China.
  • 6. School of Basic Medical, Shandong Medical and Pharmaceutical University, Yantai, China.
  • 7. School of Nursing, Zibo Polytechnic University, Zibo, China.
  • 8. Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  • 9. University of Chinese Academy of Sciences, Beijing, China.
  • 10. The Second Medical College, Shandong Medical and Pharmaceutical University, Yantai, China.
  • 11. School of Basic Medical, Shandong Medical and Pharmaceutical University, Yantai, China. [email protected].
  • 12. Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. [email protected].
  • 13. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 14. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. [email protected].
  • 15. Peninsular Cancer Center, Shandong Medical and Pharmaceutical University, Yantai, China. [email protected].
  • 16. School of Basic Medical, Shandong Medical and Pharmaceutical University, Yantai, China. [email protected].
  • 17. Shandong Key Lab of Complex Medical Intelligence and Aging, Yantai, China. [email protected].
  • # Contributed equally.
PMID: 42336842 DOI: 10.1038/s41419-026-09034-z
Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) serves as a central metabolic hub that integrates nutrient signals and orchestrates cellular metabolism to regulate many fundamental cell processes. While mTORC1 activation is known to occur both on lysosomal membranes and at the Golgi apparatus in response to environmental cues, the molecular mechanisms governing its Golgi-associated activation remain poorly understood. In this study, we identified YIF1A as a novel Golgi-localized regulator of growth factor-mediated mTORC1 signaling. Mechanistically, YIF1A interacted with the E3 ubiquitin Ligase RNF126 to facilitate K48-linked polyubiquitination of G3BP1/2, thereby promoting mTORC1 activation. Genetic depletion of either YIF1A or RNF126 stabilized G3BP1/2 proteins and significantly impaired mTORC1 activity. Notably, YIF1A knockdown conferred resistance to etoposide- and doxorubicin-induced cellular senescence. The evolutionary conservation of this pathway was demonstrated by extended or shortened lifespan in Caenorhabditis elegans lacking or overexpressing yif-1, the invertebrate ortholog of YIF1A. Our findings not only elucidate a previously unrecognized Golgi-specific regulatory axis for mTORC1 activation but also suggest YIF1A as a potential therapeutic target for modulating aging-related pathologies.

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