Kidney Week

Abstract: FR-PO271

CDK7-CDK6-FIP5 Phosphorylation Cascade Controls Axoneme Polyglutamylation and Polycystin Signaling in Primary Cilia

Session Information

• Genetic Diseases of the Kidneys: Cystic - II
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1101 Genetic Diseases of the Kidneys: Cystic

Authors

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

Kai He,

• Sun, Xiaobo, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Xiaobo Sun,

• Hu, Jinghua, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Jinghua Hu,

Background

ADPKD is mainly caused by mutations in PKD1 or PKD2, which encodes Polycystin 1 (PC1) and Polycystin 2 (PC2) respectively. PC1 and PC2 co-localize to primary cilia of kidney epithelial cells and have been proposed to form a receptor/channel complex to sense environmental cues. Recently studies suggested that many PKD mutations, especially the non-truncation mutations, cause defects in ciliary localization but not the channel activity of polycystins complex. Therefore, understanding how polycystins are targeted to and maintained in primary cilia would shed light on the etiology of ADPKD. Tubulin polyglutamylation is a spatiotemporal post-translational modification which predominantly occurs on cilia axoneme. We recently unveiled that axoneme polyglutamylation is essential for controlling the ciliary localization and dosage of PC2. Thus, axoneme polyglutamylation could be a novel target for enhancing the ciliary function of polycystins and treatment for ADPKD. However, the regulatory mechanism underlying proper axoneme polyglutamylation remains poorly understood.

Methods

Kinases library screen.
Biochemistry and Molecular biology approaches.
Cell biology approaches.
in vitro and ex vivo models of renal cystogenesis

Results

Here, were report that a ciliary CDK7-CDK6-FIP5 phosphorylation cascade specifically suppresses axoneme polyglutamylation by blocking the cilia import of glutamylases TTLL5 and TTLL6. Excitingly, pharmacologic inhibition of CDK6 by Abemaciclib effectively restores axoneme polyglutamylation and ciliary levels of PC2 in Cep41 and Armc9-deficient cells, the Joubert syndrome genes whose mutations cause axoneme hypoglutamylation. Interestingly, CDK6 is abnormally upregulated in human ADPKD cells, renal tubules of ADPKD mouse model (Pkd1^RC/RC mice), and ADPKD patients. Remarkably, pharmacologic inhibition of CDK6 significantly suppressed the cyst growth in in vitro and ex vivo models of renal cystogenesis.

Conclusion

Our study reveals the regulatory mechanism of axoneme polyglutamylation and ciliary polycystin signaling, and suggests CDK6 as a potential therapeutic target for ADPKD.

Funding

• NIDDK Support