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Kidney Week

Abstract: FR-PO141

Primary Cilia Control Senescence Initiation in Stressed Renal Epithelial Cells

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Hao, Jielu, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Ma, Xiaoyu, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Zhang, Yingyi, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Hu, Jinghua, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Cellular senescence is an irreversible proliferative arrest that reduces regenerative capacity of kidney after insults. Senescent cells may further exacerbate kidney injury by releasing pro-inflammatory senescent-associated-secretory phenotype (SASP). The molecular mechanism underlying stress-induced senescence remains poorly understood. Here, we discovered a direct cilium-nuclear axis in initiating senescence responses in renal tubular epithelial cells upon DNA damage.


Human renal cortical tubular epithelial cells (RCTE) were exposed with 5 Gy by the X-ray irradiator to induce senescence. Senescent level was determined by measuring Senescent Associated (SA)-b-Gal staining, protein and RNA levels of SASP markers. Essential cilia gene IFT88 was knocked down to disrupt ciliogenesis in RCTE cells. Cas9 cell lines were generated to study knockout phenotypes. The expression and localization of key components were measured by western blotting, confocoal imaging, and super-reslolution Structure Illumination Microscopy. Immunoprecipitation assay and GST pull-down assay were performed to analyze protein-protein interaction.


Using immunofluorescence, we observed that irradiation (IR) induces robust but transient ciliogenesis in RCTE cells during senescence, which accompanied by downregulation of ciliary GTPases ARL13B and ARL3 and upregulation of transition fiber protein FBF1. Upon DNA damage, FBF1 translocates from primary cilia to promyelocytic leukemia nuclear bodies (PML-NBs), a nuclear structure implicated in senescence regulation, to initiate senescence in stressed cells. Mechanistically, we discovered that the ARL13B-ARL3 GTPase cascade negatively regulates UBC9-mediated SUMOylation of FBF1 at the ciliary base in normal cells, whereas irreparable stresses suppress ARL expression and thus enhance FBF1 SUMOylation in stressed cells. SUMOylated FBF1 translocates from primary cilia to PML-NBs. FBF1 depletion abolishes stress-induced PML-NB upregulation and senescence initiation, whereas FBF1 overexpression causes opposite effects.


Our findings define a paradigm in which sensory cilia communicate directly with the nucleus to control senescence initiation in stressed renal tubular epithelial cells. These results further highlight the potential of targeting cilia in future senescence-related therapeutic strategies in kidney diseases.