Abstract: FR-PO564
CDK6 Suppresses Tubulin Polyglutamylation in Primary Cilia and Promotes Renal Cystogenesis in ADKPD
Session Information
- Genetic Diseases: Cystic - Basic
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
Authors
- He, Kai, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Sun, Xiaobo, 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
- Hu, Jinghua, Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background
Polycystin-1 (PC1) and Polycystin-2 (PC2) hypothetically forming an ion channel complexes localize on primary cilium to inhibit renal cyst growth. Polyglutamylation (PG) is one of the tubulin posttranslational modifications (PTMs) predominantly occurs on cilia axoneme which controls the ciliary localization of PC1/2. Defective axoneme PG has been correlated with ciliopathies that usually manifest syndromic forms of PKD. We recently discovered an uncanonical CDK6-mediated pathway that specifically inhibits axoneme PG by engaging the ciliary import of tubulin glutamylases. Intriguingly, CDK6 is strongly upregulated in the renal tubules of ADPKD mice and human patients. In agreement with the inhibitory role of CDK6 in ciliary import of tubulin glutamylases, defective axoneme PG was observed in ADPKD cells. Remarkably, pharmacologic inhibition of CDK6 restores defective axoneme PG, increase ciliary dosage of PC2 in ADPKD cells, and significantly suppressed the cyst growth in the ex vivo model of ADPKD. These data suggest that targeting axoneme PG could be a novel therapeutic approach for ADPKD. To identify novel small molecules/drugs to specifically target axoneme PG, we established high-content image-based strategy to screen drug-repurposing compound library and kinase inhibitor library. We will further access the therapeutic potential of drug hits in ADPKD, using in vitro, ex vivo and in vivo ADPKD models.
Methods
Cell-imaging
Drug screening
Biochemstry and Molecular Biology
Ex vivo renal cystogenesis
Results
1. CDK6 suppresses tubulin polyglutamylation by inhibiting ciliary import of tubulin glutamylases.
2. CDK6 is strongly upregulated in renal tubules of ADPKD mice and human patients.
3. ADPDK cells exhibit defective tubulin polyglutamylation in primary cilia.
4. Inhibition of CDK6 suppresses cyst growth in ex vivo ADPKD model.
Conclusion
Targeting axoneme PG could be a novel therapeutic approach for ADPKD.
Funding
- NIDDK Support