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Phenotypes

Mouse phenotype:

increased circulating alanine transaminase level

Subcellular localization

cilia

Functional category

• Ciliary assembly/disassembly

Function

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(41086943). We found that polycystin-2, but not smoothened or fibrocystin, requires the biogenesis of lysosome-related organelles complex-1 (BLOC-1) for ciliary delivery. Consistent with the role of BLOC-1 in sorting from the endosome, we find that disrupting the recycling endosome reduces ciliary polycystin-2 and causes its accumulation in the recycling endosome. This is the first demonstration of a role for BLOC-1 in ciliary assembly and highlights the complexity of pathways taken to the cilium(28576874).