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A stress-induced cilium-to-PML-NB route drives senescence initiation

Author

Listed:
  • Xiaoyu Ma

    (Mayo Clinic)

  • Yingyi Zhang

    (Mayo Clinic)

  • Yuanyuan Zhang

    (ShengJing Hospital of China Medical University)

  • Xu Zhang

    (Mayo Clinic
    Mayo Clinic)

  • Yan Huang

    (Mayo Clinic)

  • Kai He

    (Mayo Clinic)

  • Chuan Chen

    (Mayo Clinic)

  • Jielu Hao

    (Mayo Clinic)

  • Debiao Zhao

    (Mayo Clinic)

  • Nathan K. LeBrasseur

    (Mayo Clinic
    Mayo Clinic
    Mayo Clinic)

  • James L. Kirkland

    (Mayo Clinic)

  • Eduardo N. Chini

    (Mayo Clinic
    Mayo Clinic)

  • Qing Wei

    (Chinese Academy of Sciences (CAS))

  • Kun Ling

    (Mayo Clinic)

  • Jinghua Hu

    (Mayo Clinic
    Mayo Clinic
    Mayo Clinic)

Abstract

Cellular senescence contributes to tissue homeostasis and age-related pathologies. However, how senescence is initiated in stressed cells remains vague. Here, we discover that exposure to irradiation, oxidative or inflammatory stressors induces transient biogenesis of primary cilia, which are then used by stressed cells to communicate with the promyelocytic leukemia nuclear bodies (PML-NBs) to initiate senescence responses in human cells. Mechanistically, a ciliary ARL13B-ARL3 GTPase cascade negatively regulates the association of transition fiber protein FBF1 and SUMO-conjugating enzyme UBC9. Irreparable stresses downregulate the ciliary ARLs and release UBC9 to SUMOylate FBF1 at the ciliary base. SUMOylated FBF1 then translocates to PML-NBs to promote PML-NB biogenesis and PML-NB-dependent senescence initiation. Remarkably, Fbf1 ablation effectively subdues global senescence burden and prevents associated health decline in irradiation-treated mice. Collectively, our findings assign the primary cilium a key role in senescence induction in mammalian cells and, also, a promising target in future senotherapy strategies.

Suggested Citation

  • Xiaoyu Ma & Yingyi Zhang & Yuanyuan Zhang & Xu Zhang & Yan Huang & Kai He & Chuan Chen & Jielu Hao & Debiao Zhao & Nathan K. LeBrasseur & James L. Kirkland & Eduardo N. Chini & Qing Wei & Kun Ling & J, 2023. "A stress-induced cilium-to-PML-NB route drives senescence initiation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37362-7
    DOI: 10.1038/s41467-023-37362-7
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    References listed on IDEAS

    as
    1. Qing Wei & Yingyi Zhang & Clementine Schouteden & Yuxia Zhang & Qing Zhang & Jinhong Dong & Veronika Wonesch & Kun Ling & Alexander Dammermann & Jinghua Hu, 2016. "The hydrolethalus syndrome protein HYLS-1 regulates formation of the ciliary gate," Nature Communications, Nature, vol. 7(1), pages 1-10, November.
    2. Mark Pearson & Roberta Carbone & Carla Sebastiani & Mario Cioce & Marta Fagioli & Shin’ichi Saito & Yuichiro Higashimoto & Ettore Appella & Saverio Minucci & Pier Paolo Pandolfi & Pier Giuseppe Pelicc, 2000. "PML regulates p53 acetylation and premature senescence induced by oncogenic Ras," Nature, Nature, vol. 406(6792), pages 207-210, July.
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    Cited by:

    1. Jielu Hao Robichaud & Yingyi Zhang & Chuan Chen & Kai He & Yan Huang & Xu Zhang & Xiaobo Sun & Xiaoyu Ma & Gary Hardiman & Ciaran G. Morrison & Zheng Dong & Nathan K. LeBrasseur & Kun Ling & Jinghua H, 2024. "Transiently formed nucleus-to-cilium microtubule arrays mediate senescence initiation in a KIFC3-dependent manner," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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