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Kidney Week

Abstract: FR-PO962

Targeting Axoneme Polyglutamylation as a Potential Therapeutic Approach for ADPKD Treatment

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • He, Kai, Mayo Clinic , Rochester, Minnesota, United States

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorders, causing uncontrolled growth of cysts in kidney eventually leading to kidney failure. Primary cilia, the non-motile sensory devices on most cell surfaces, have been suggested as the key organelles in the pathogenesis of ADPKD. Proper targeting/maintenance of Polycystin 1(PC1)/ Polycystin 2(PC2) heterodimer on cilia surface are critical for cilia as mechano-sensor. Dysfunctional polycystins would compromise cilia-dependent signaling in maintaining normal nephron structure and lead to cystogenesis. Recently, accumulating evidence suggest a link between the level of functional Polycystins and disease severity, indicative of a dosage model of cystogenesis in ADPKD. Theoretically, restoring the functional level of cilia polycystins is a promising therapeutic strategy to delay or even prevent the cystogenesis. However, perusing this strategy is impeded by the lack of understanding of how the ciliary targeting/maintenance of polycystins is controlled.


1. Immunoprecipitation and GST pull-down.
2. MDCK cyst formation in 3D culture.
3. Immunofluorescence microscopy.
4. Live-cell imaging.
5. Western blotting.
6. Bio-ID.


Axoneme polyglutamylation is specifically regulated by a Joubert syndrome protein ARL13B and tuned by the balance of glutamylases TTLL5/6 and deglutamylase CCP5. ARL13B interacts with RAB11 effector FIP5 to promote the ciliary import of glutamylases. Hypoglutamylation caused by a deficient FIP5-regulated trafficking impairs the proper anchoring of PC2 in cilia. Remarkably, depletion of CCP5 effectively promotes hyperglutamylation and restores the ciliary PC2 in GANAB-/- cells. By implementing axoneme polyglutamylation as readout, we initiated a preliminary imaging-based drug screen. We identified several hits which could induce axoneme hyperglutamylation and increase PC2 dosage and, importantly, suppress MDCK cyst formation in 3D culture, implicating the therapeutic potential of targeting axoneme polyglutamylation for ADPKD.


1. ARL13B-FIP5-regulated ciliary import of glutamylases is essential for axoneme polyglutamylation.
2. Axoneme polyglutamylation anchors ciliary PC2.
3. Restoring ciliary polycystins by increasing axoneme polyglutamylation could be a potential therapeutic approach for ADPKD treatment.


  • NIDDK Support