Transiently formed nucleus-to-cilium microtubule arrays mediate senescence initiation in a KIFC3-dependent manner

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2024年9月12日

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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 Hu

摘要

Despite the importance of cellular senescence in human health, how damaged cells undergo senescence remains elusive. We have previously shown that promyelocytic leukemia nuclear body (PML-NBs) translocation of the ciliary FBF1 is essential for senescence induction in stressed cells. Here we discover that an early cellular event occurring in stressed cells is the transient assembly of stress-induced nucleus-to-cilium microtubule arrays (sinc-MTs). The sinc-MTs are distinguished by unusual polyglutamylation and unique polarity, with minus-ends nucleating near the nuclear envelope and plus-ends near the ciliary base. KIFC3, a minus-end-directed kinesin, is recruited to plus-ends of sinc-MTs and interacts with the centrosomal protein CENEXIN1. In damaged cells, CENEXIN1 co-translocates with FBF1 to PML-NBs. Deficiency of KIFC3 abolishes PML-NB translocation of FBF1 and CENEXIN1, as well as senescence initiation in damaged cells. Our study reveals that KIFC3-mediated nuclear transport of FBF1 along polyglutamylated sinc-MTs is a prerequisite for senescence induction in mammalian cells.