title: Polycystin-1 surface localization is stimulated by polycystin-2 and cleavage at the G protein-coupled receptor proteolytic site.
abstract: Polycystin (PC)1 and PC2 are membrane proteins implicated in autosomal dominant polycystic kidney disease. A physiologically relevant cleavage at PC1's G protein-coupled receptor proteolytic site (GPS) occurs early in the secretory pathway. Our results suggest that PC2 increases both PC1 GPS cleavage and PC1's appearance at the plasma membrane. Mutations that prevent PC1's GPS cleavage prevent its plasma membrane localization. PC2 is a member of the trp family of cation channels and is an important PC1 binding partner. The effect of PC2 on PC1 localization is independent of PC2 channel activity, as tested using channel-inhibiting PC2 mutations. PC1 and PC2 can interact through their C-terminal tails, but removing the C-terminal tail of either protein has no effect on PC1 surface localization in human embryonic kidney 293 cells. Experiments in polarized LLC-PK cells show that apical and ciliary PC1 localization requires PC2 and that this delivery is sensitive to PC2 truncation. In sum, our work shows that PC2 expression is required for the movement of PC1 to the plasma and ciliary membranes. In fibroblast cells this localization effect is independent of PC2's channel activity or PC1 binding ability but involves a stimulation of PC1's GPS cleavage before the PC1 protein's surface delivery.
authors.affiliation: Departments of Cell Biology and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Chapin
authors.forename: Vanathy
authors.initials: V
authors.lastname: Rajendran
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Caplan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane; D002923:Cilia / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D018374:LLC-PK1 Cells; D009154:Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D013552:Swine; D050396:TRPP Cation Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D050396:TRPP Cation Channels