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Kidney Week

Abstract: FR-PO157

Transient Nucleus-to-Cilium Microtubule Assemblies Initiate Senescence in Stressed Renal Epithelial Cells

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Robichaud, Jielu Hao, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Zhang, Yingyi, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • He, Kai, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Chen, Chuan, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Huang, Yan, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Dong, Zheng, Augusta University, Augusta, Georgia, United States
  • Ling, Kun, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Hu, Jinghua, Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background

Cellular senescence plays a critical role in diminishing regenerative capacity and exacerbating kidney injury. In previous research, we demonstrated that the translocation of a ciliary protein, FBF1, to promyelocytic leukaemia nuclear bodies (PML-NBs) is crucial for inducing senescence in stressed human cells. However, how FBF1 translocates into the nucleus upon exposure to stressors remain elusive.

Methods

Human renal cortical tubular epithelial cells (RCTE) were exposed with irradiation, inflammatory cytokines, or oxidative stress to induce cellular senescence. Senescent level was determined using Senescent Associated (SA)-b-Gal staining, and protein and RNA levels of senescence and SASP markers. Immunofluorescence was employed to detect sinc-MTs. Microtubule assembly was disrupted in RCTE cells using Colchicine or knockdown CDK5RAP2. Knockdown of the tubulin glutamylases were performed to investigate the role of polyglutamylation in sinc-MT-mediated senescence induction. Western blotting, confocal imaging, and super-resolution Structure Illumination Microscopy (SIM) were used to determine the expression and subcellular localization of key components. Protein-protein interaction were analyzed through APEX2 based BioID analysis and confirmed by exogenous and endogenous immunoprecipitation assays.

Results

Here, we discovered a novel phenomenon that, in renal epithelial cells, irreparable stressors induce a transient assembly of nucleus-to-cilium microtubule assays (sinc-MTs), which are highly polyglutamylated, unconventionally polarized with minus-ends nucleating near the nuclear envelope and plus-ends anchored below the ciliary base. KIFC3, a minus-end-directed kinesin, is recruited to cilia base in stressed cells and use centrosomal protein CENEXIN1 as an adaptor to translocate FBF1 towards the nucleus along sinc-MTs. Deficiency of KIFC3 or CENEXIN1 abolishes both FBF1 translocation and senescence initiation in stressed cells.

Conclusion

Collectively, we elucidate the mechanistic insights into the essential role of a stress-induced sinc-MTs in transducing stress-induced ciliary signals into the nucleus to initiate senescence program in damaged renal epithelial cells. Our findings highlight the potential of targeting cilia as a therapeutic strategy for senescence-related kidney diseases.