Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
Department of Clinical Genetics, ShengJing Hospital of China Medical University, Shenyang, Liaoning, China.
Nat Commun. 2023 Apr 3;14(1):1840. doi: 10.1038/s41467-023-37362-7.
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.
细胞衰老有助于组织稳态和与年龄相关的病理。然而，在应激细胞中衰老如何被引发仍然不清楚。在这里，我们发现，暴露于辐射、氧化或炎症应激源会诱导初级纤毛的短暂生物发生，然后应激细胞利用这些初级纤毛与早幼粒细胞白血病核体（PML-NBs）进行通讯，从而在人类细胞中引发衰老反应。在机制上，纤毛 ARL13B-ARL3 GTPase 级联反应负调节转换纤维蛋白 FBF1 和 SUMO 连接酶 UBC9 的结合。不可修复的应激会下调纤毛 ARL，并将 UBC9 释放到纤毛基底以 SUMO 化 FBF1。SUMO 化的 FBF1 随后易位到 PML-NBs 以促进 PML-NB 的生物发生和 PML-NB 依赖性衰老的起始。值得注意的是，Fbf1 缺失有效地抑制了整体衰老负担，并防止了辐照处理小鼠相关的健康下降。总的来说，我们的发现赋予了初级纤毛在哺乳动物细胞衰老诱导中的关键作用，也是未来衰老治疗策略中的一个有希望的靶点。
