The Ion channel, CFTR, assembles with HIPPO pathway proteins TAZ and YAP in polycystic kidney disease.

Adult-onset polycystic kidney disease (ADPKD) leads to a decline in renal function. Cyst expansion is critically dependent on increased proliferation(1). Because proliferation is so central to cyst formation, thwarting these processes is critical for improving the health of patients with ADPKD. We have shown that the CFTR modulator VX-809 reduces cyst formation by creating an absorptive phenotype and inhibiting proliferation. We utilized the pkd1R3277/R3277C (RC) mutant mice and cell lines to study this phenomenon. We show that CFTR closely associates with the HIPPO pathway proteins TAZ and YAP. CFTR co-localizes strongly with TAZ and YAP in normal and RC mice and in RC mice treated with VX-809. In RC mice, the co-localization of TAZ, YAP, and CFTR is predominately at the apical membrane; the abnormal accumulation of these three proteins at the apical membrane is indicative of their role in cyst growth. VX-809 treatment of RC kidneys restores CFTR, TAZ, and YAP to a basolateral location similar to that observed in the normal kidney. CFTR, TAZ, and YAP also co-localize with calnexin, a marker of the ER, with the highest co-localization in untreated RC kidneys. We show that both TAZ and YAP are increased in the nuclei of untreated RC kidneys when compared to normal kidneys. Importantly, 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.