UC Santa Barbara

Mutations in the gene encoding polycystin-1 (PC1) are the most common cause of autosomal dominant polycystic kidney disease (ADPKD). Cysts in ADPKD exhibit a Warburg-like metabolism characterized by dysfunctional mitochondria and aerobic glycolysis. PC1 is an integral membrane protein with a large extracellular domain, a short C-terminal cytoplasmic tail and shares structural and functional similarities with G protein-coupled receptors (GPCRs). Its exact function remains unclear. The C- terminal cytoplasmic tail of PC1 undergoes proteolytic cleavage, generating soluble fragments that are overexpressed in ADPKD kidneys. The regulation, localization, and function of these fragments is poorly understood. Here, we show that a ~30 kDa cleavage fragment (PC1-p30), comprising the entire C-terminal tail, undergoes rapid proteasomal degradation by a mechanism involving the von Hippel-Lindau tumor suppressor protein (pVHL). PC1-p30 is stabilized by reactive oxygen species (ROS), and the subcellular localization is regulated by ROS in a dose-dependent manner. We found that a second, ~15 kDa fragment (PC1-p15), is generated by caspase cleavage at a conserved site (Asp-4195) on the PC1 C-terminal tail. PC1-p15 is not subject to degradation and constitutively localizes to the mitochondrial matrix. Both cleavage fragments induce mitochondrial fragmentation, and PC1-p15 expression causes impaired fatty acid oxidation and increased lactate production, indicative of a Warburg- like phenotype. Endogenous PC1 tail fragments accumulate in renal cyst-lining cells in a mouse model of PKD. Another hallmark of ADPKD is dedifferentiation as an initiating step of renal tubular cells to form cysts. Loss of functional PC1 signaling is associated with the concomitant loss of cell-cell junctions. We show that expressing PC1-p15 leads to loss of the epithelial adhesion marker E-cadherin and resulting morphological changes of adherens junctions. Collectively, these results identify novel mechanisms regarding the regulation and function of PC1, and suggest that C- terminal PC1 fragments may be involved in the mitochondrial and metabolic abnormalities as well as the loss of adherens junctions observed in ADPKD.