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

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 () and Jinghua Hu ()
Additional contact information
Xiaoyu Ma: Mayo Clinic
Yingyi Zhang: Mayo Clinic
Yuanyuan Zhang: ShengJing Hospital of China Medical University
Xu Zhang: 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
James L. Kirkland: Mayo Clinic
Eduardo N. Chini: Mayo Clinic
Qing Wei: Chinese Academy of Sciences (CAS)
Kun Ling: Mayo Clinic
Jinghua Hu: Mayo Clinic

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37362-7

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