Kidney Week

Abstract: SA-PO0137

CFTR Assembles into Multiple Protein Complexes in the Kidney That Regulate Proliferation and Protein Trafficking to the Cilia in ADPKD

Session Information

• ADPKD and Cystic Kidney Disease - 3
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Cebotaru, Liudmila, Johns Hopkins Medicine, Baltimore, Maryland, United States

Liudmila Cebotaru, MD

• Sharma, Abhishek, Johns Hopkins Medicine, Baltimore, Maryland, United States

Abhishek Sharma, PhD

• Afshani, Masoud, Johns Hopkins Medicine, Baltimore, Maryland, United States

Masoud Afshani, PhD, DVM

• Sharma, Tanvi, Johns Hopkins Medicine, Baltimore, Maryland, United States

Tanvi Sharma, PhD

• Guggino, William B., Johns Hopkins Medicine, Baltimore, Maryland, United States

William B. Guggino, PhD

Background

Adult-onset dominant polycystic kidney disease (ADPKD) leads to a decline in renal function through multiple mechanisms involving multiple misregulated signal transduction mechanisms both in the cytoplasm and primary cilium. We have strong evidence that CFTR modulators rescue multiple facets of the pathophysiology of ADPKD. The question is how can altering CFTR affect multiple mechanisms in ADPKD. We show here that CFTR is a member of multiple protein complexes involving the HIPPO pathway that regulates proliferation and the SEPTIN 2 proteins that regulate protein trafficking to the primary cilium and that restoring these is therapeutic.

Methods

We used immunoprecipitation and proximity ligase assays (PLA) combined with immunofluorescence experiments in pkd1^{R3277/ R3277C} (RC) mutant mice and cell lines treated with the CFTR modulators such as VX-809.

Results

In RC mice, the co-localization of the HIPPO proteins, TAZ and YAP and the cytoskeletal GTP-binding protein, SETPIN 2, and CFTR is strongly at the apical membrane; the abnormal accumulation of these four proteins at the apical membrane is indicative of their role in cyst growth and cilial protein trafficking. VX-809 treatment restores CFTR, TAZ, YAP and SEPTIN 2 to their locations. We show that both TAZ and YAP are increased in the nuclei of untreated RC kidneys as compared to normal kidneys. VX-809 reduces TAZ and YAP in the nucleus to levels comparable to those in normal kidneys, providing mechanistic insight into how CFTR modulator therapy reduces proliferation. The PLA assays show highly abnormal interactions of CFTR with SEPTIN 2 that mis-regulate the trafficking of PC2 to the cilium and that when corrected with CFTR modulators PC2 is restored to the primary cilium. Finally, we found that the interactions of CFTR with scaffold proteins NHERF 1 & 2 are also abnormal in ADPKD suggesting that CFTR’s interaction with TAZ and YAP mostly involves the NHERF proteins via CFTR’s PDZ binding domain.

Conclusion

We provide here an understanding of how CFTR via complex interactions with multiple pathways through molecular interactions can affect proliferation and protein trafficking to the primary cilium highlighting its function both as a chloride channel and conductance regulator and providing an understanding of how CFTR modulators can be therapeutic.

Funding

• NIDDK Support