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Retromer associates with the cytoplasmic amino-terminus of polycystin-2
Frances C Tilley1, Matthew Gallon1, Chong Luo2,3
1School of Biochemistry, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
Insights
Autosomal dominant polycystic kidney disease (ADPKD) involves mutations in PKD1 or PKD2. This study identifies polycystin-2 (PC2) as a cargo protein for the retromer complex, crucial for protein trafficking in ADPKD.
Area of Science:
- Cell Biology
- Genetics
- Molecular Medicine
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent monogenic disorder affecting millions globally.
- ADPKD stems from mutations in PKD1 or PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2).
- Altered intracellular trafficking of PC1 and PC2 is a hallmark of ADPKD, yet transport mechanisms are not fully understood.
Purpose of the Study:
- To investigate the mechanisms governing vesicular transport of polycystins in ADPKD.
- To identify novel protein interactions involved in PC1 and PC2 trafficking.
- To elucidate the role of the retromer complex in polycystin trafficking.
Main Methods:
- Co-immunoprecipitation assays to detect protein-protein interactions.
- Immunofluorescence microscopy to visualize protein localization.
- Analysis of protein trafficking in response to genetic manipulation.
Main Results:
- A direct interaction between polycystin-2 (PC2) and the retromer complex was identified.
- PC2 associates with retromer via its cytoplasmic amino-terminal domain.
- Disruption of PC2-retromer interaction leads to reduced ciliary levels of PC1.
Conclusions:
- Polycystin-2 (PC2) is identified as a cargo protein of the retromer complex.
- This interaction is critical for maintaining normal polycystin levels and cellular function.
- Findings provide new insights into ADPKD pathogenesis and potential therapeutic targets.
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic human disease, with around 12.5 million people affected worldwide. ADPKD results from mutations in either PKD1 or PKD2, which encode the atypical G-protein coupled receptor polycystin-1 (PC1) and the transient receptor potential channel polycystin-2 (PC2), respectively. Although altered intracellular trafficking of PC1 and PC2 is an underlying feature of ADPKD, the mechanisms which govern vesicular transport of the polycystins through the biosynthetic and endosomal membrane networks remain to be fully elucidated. Here, we describe an interaction between PC2 and retromer, a master controller for the sorting of integral membrane proteins through the endo-lysosomal network. We show that association of PC2 with retromer occurs via a region in the PC2 cytoplasmic amino-terminal domain, independently of the retromer-binding Wiskott-Aldrich syndrome and scar homologue (WASH) complex. Based on observations that retromer preferentially interacts with a trafficking population of PC2, and that ciliary levels of PC1 are reduced upon mutation of key residues required for retromer association in PC2, our data are consistent with the identification of PC2 as a retromer cargo protein.This article has an associated First Person interview with the first author of the paper.
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