Mispolarization of desmosomal proteins and altered intercellular adhesion in autosomal dominant polycystic kidney disease.
Polycystin-1, the product of the major gene mutated in autosomal dominant polycystic kidney disease (ADPKD), has been shown to associate with multiple epithelial cell junctions. Our hypothesis is that polycystin-1 is an important protein for the initial establishment of cell-cell junctions and maturation of the cell and that polycystin-1 localization is dependent on the degree of cell polarization. Using laser-scanning confocal microscopy and two models of cell polarization, polycystin-1 and desmosomes were found to colocalize during the initial establishment of cell-cell contact when junctions were forming. However, colocalization was lost in confluent monolayers. Parallel morphological and biochemical evaluations revealed a profound mispolarization of desmosomal components to both the apical and basolateral domains in primary ADPKD cells and tissue. Studies of the intermediate filament network associated with desmosomes showed that there is a decrease in cytokeratin levels and an abnormal expression of the mesenchymal protein vimentin in the disease. Moreover, we show for the first time that the structural alterations seen in adherens and desmosomal junctions have a functional impact, leaving the ADPKD cells with weakened cell-cell adhesion. In conclusion, in this paper we show that polycystin-1 transiently colocalizes with desmosomes and that desmosomal proteins are mislocalized as a consequence of polycystin-1 mutation.
Silberberg
Melina
M
Dept. of Pathology MSC08-4640, 2325 Camino de Salud CRF 225, Univ. of New Mexico Health Sciences Center, Albuquerque, NM 87131-5301, USA.
Charron
Audra J
AJ
Bacallao
Robert
R
Wandinger-Ness
Angela
A
D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology; D002478:Cells, Cultured; D003896:Desmosomes / Q000378:metabolism / Q000473:pathology*; D010450:Endopeptidases / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism* / Q000473:pathology*; D011506:Proteins / Q000378:metabolism; D050396:TRPP Cation Channels
D002118:Calcium; D010450:Endopeptidases; D007381:Intermediate Filament Proteins; D011506:Proteins; D050396:TRPP Cation Channels; C023139:dispase