Interaction Proteomics of Polycystins 1 and 2 Reveal a Novel Role for the BLOC-1/BORC Lysosomal Positioning Complex

PKD1 and PKD2 are the most commonly mutated genes in autosomal dominant polycystic kidney disease (ADPKD). However, the precise roles of the encoded polycystin 1/2 (PC1 and PC2) proteins, and how their functions are disrupted in ADPKD, remain unclear. Here, we characterize the protein interaction networks of PC1 and PC2 in cycling and ciliated cells using proximity-dependent biotinylation (BioID), identifying a common set of 172 proteins that interact with the C terminus of PC1 and the full-length PC2 protein, enriched in autophagy regulators, endoplasmic reticulum tethers, endoplasmic reticulum stress proteins, and other proteins previously linked to ADPKD. Notably, we also find that PC1 specifically interacts with ciliary and lysosomal proteins, including components of the biogenesis of lysosome-related organelles complex (BLOC-1) and BLOC-one-related-complex (BORC). BLOC-1/BORC colocalizes with PC1 at lysosomes and cilia and is required for proper ciliary PC1 localization. In addition, PC1 mutant kidney cells derived from an ADPKD patient display defects in BLOC-1/BORC distribution. Renal cells depleted of PC1 exhibit abnormal lysosomal distribution, similar to those depleted of BLOC-1/BORC components. Finally, shRNA knockdown of BLOC-1/BORC components promoted cystogenesis in a 3D in vitro cyst model, and this could be attenuated by heterologous expression of the C terminus of PC1. This rich dataset thus links the BLOC-1/BORC complex to PC1 function and can be further mined for additional mechanistic insights into the PC1/2 ADPKD proteins.