Compromised Cytoarchitecture and Polarized Trafficking in Autosomal Dominant Polycystic Kidney Disease Cells

Cystogenesis associated with autosomal dominant polycystic kidney disease (ADPKD) is characterized by perturbations in the polarized phenotype and function of cyst-lining epithelial cells. The polycystins, the protein products of the genes mutated in the majority of ADPKD cases, have been described...

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Bibliographic Details
Published in:The Journal of cell biology 2000-04, Vol.149 (1), p.111-124
Main Authors: Charron, Audra J., Nakamura, Sakie, Bacallao, Robert, Wandinger-Ness, Angela
Format: Article
Language:English
Subjects:
Autosomal dominant polycystic kidney
Biological Transport
Cadherins
Cadherins - metabolism
Carrier Proteins - metabolism
Cell Adhesion
Cell Membrane - chemistry
Cell Membrane - metabolism
Cell membranes
Cell Polarity
Cells
Cells, Cultured
Cytoskeleton - metabolism
Cytoskeleton - pathology
Disease
Epithelial cells
Epithelial Cells - pathology
Exocytosis
Fluorescent Antibody Technique
Genes, Dominant - genetics
Golgi apparatus
Golgi Apparatus - metabolism
Humans
Kidney cells
Kidneys
Kinetics
Membrane proteins
Membrane Proteins - genetics
Membrane Proteins - physiology
Membranes
Mutation
Original
Polycystic kidney diseases
Polycystic Kidney, Autosomal Dominant - genetics
Polycystic Kidney, Autosomal Dominant - metabolism
Polycystic Kidney, Autosomal Dominant - pathology
Protein Binding
Protein Processing, Post-Translational
Proteins - genetics
Proteins - physiology
Tight Junctions - metabolism
TRPP Cation Channels
Vesicular Transport Proteins
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Description
Summary:Cystogenesis associated with autosomal dominant polycystic kidney disease (ADPKD) is characterized by perturbations in the polarized phenotype and function of cyst-lining epithelial cells. The polycystins, the protein products of the genes mutated in the majority of ADPKD cases, have been described recently, but the pathological mechanism by which causal mutations result in the mislocalization of cell membrane proteins has remained unclear. This report documents the dissociation from the ADPKD cell basolateral membrane of three molecules essential for spatial organization and exocytosis. The adherens junction protein E-cadherin, the subcellular disposition of which governs intercellular and intracellular architecture, was discovered sequestered in an internal ADPKD cell compartment. At the same time, sec6 and sec8, components of a complex critical for basolateral cargo delivery normally arrayed at the apico-lateral apex, were depleted from the ADPKD cell plasma membrane. An analysis of membrane transport revealed that basolateral trafficking of proteins and lipids was impaired as a result of delayed cargo exit from the ADPKD cell Golgi apparatus. Apical transport proceeded normally. Taken together with recent documentation of an association between polycystin-1 and E-cadherin (Huan and van Adelsberg, 1999), the data suggest that causal mutations disrupt E-cadherin-dependent cytoarchitecture, adversely affecting protein assemblies crucial for basolateral trafficking.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.149.1.111