Valosin-containing protein in ciliary morphology: a novel target in ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder leading to kidney cyst formation and loss of kidney function. The major causative genes Pkd1 and Pkd2 encode for the ciliary proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively, which are involved in ciliary functions. Within PKD1-defective cells, the accumulation of misfolded PC1 proteins triggers the unfolded protein response (UPR). Among the pathways activated, the ER-associated degradation (ERAD), mediated by proteins such as valosin-containing protein (VCP), aims to alleviate the unfolded or misfolded protein burden. Our study investigates the genetic relationship between VCP and PC1-dependent cystogenesis. We found that the pharmacological inhibition of VCP ameliorates the cystic phenotype in Pkd1-knockout mice. This effect is associated with increased ER stress-dependent apoptosis in PC1-deficient cells. In addition, we discovered that VCP is localized in the primary cilia and its inhibition affects cilia assembly and reduces the cilia length.NEW & NOTEWORTHY Our findings identify VCP as a novel ciliary protein and a potential therapeutic target for ADPKD. We confirmed that VCP inhibition reduces cyst burden in vivo and selectively induces apoptosis in PC1-deficient cells in vitro via UPR-activation. In addition, VCP regulates cilia assembly and morphology, binding together proteostasis and ciliary dynamics. The results of this study support VCP as a modulator of cystogenesis and offer a novel therapeutical strategy for ADPKD. By selectively promoting apoptosis in PC1-deficient cells and modulating their ciliary functions, VCP inhibition may offer a novel approach to treat ADPKD.