Mispolarization of desmosomal proteins and altered intercellular adhesion in autosomal dominant polycystic kidney disease

Abstract

cystin-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.

Restoration of desmosomal junction protein expression and inhibition of H3K9-specific histone demethylase activity by cytostatic proline-rich polypeptide-1 leads to suppression of tumorigenic potential in human chondrosarcoma cells

“…Dispase assay was performed as previously described (19). Dispase II was supplied by Roche Life Science, Indianapolis, IN (04942078001).…”

Ciliary dysfunction in polycystic kidney disease: an emerging model with polarizing potential

“…Polycystin-1 localizes to the desmosomes at the lateral membranes soon after establishment of cell-cell junctions (14,91,97). When cell polarity is achieved and cellular differentiation begins, polycystin-1 appears to interact with the tight junctional proteins E-cadherin and the catenins (98).…”

“…This reductionist-like approach and its conclusions based on a cellular organelle with unknown functions in the human kidney is risky, because it fails to integrate the data from other studies showing the other cellular localizations and functions for polycystins, protein products of PKD genes (6)(7)(8)(9)(10)(11)(12)(13)(14)(15), as well as other cystic disease proteins (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Furthermore, functional data for proteins in the ciliary plasma membrane is limited.…”

“…Localization does not directly imply importance; otherwise, the endoplasmic reticulum and Golgi apparatus, which certainly contain all of these proteins, should be equally as "guilty". However, proteins associated with the human cystic diseases of the kidney (such as fibrocystin, nephronophthisis-1 to 5, polycystin-1 and -2) also localize to the lateral junctions with many of these proteins having other subcellular localizations and function (6,14,27). Moreover, proteins such as Kif3A/B, polaris, and cystin exclusively localize to the cilium-basal bodycentriole axis, and when mutated in mice cause PKD.…”

Homophilic and heterophilic polycystin 1 interactions regulate E-cadherin recruitment and junction assembly in MDCK cells

“…In human cystic cells, the absence of surface PC1 is associated with concomitant loss of surface E-cadherin expression and its replacement by N-cadherin (Streets et al, 2003;Roitbak et al, 2004;Russo et al, 2005). A putative role for PC1 in desmosome function has also been postulated because of its immunolocalisation to desmosomal junctions, the mislocalisation of desmosome junction proteins in cystic cells and the reported interaction of the PC1 C-terminus with intermediate filaments (Scheffers et al, 2000;Xu et al, 2001;Russo et al, 2005;Silberberg et al, 2005). However, two studies reporting the timing of PC1 and desmoplakin recruitment after a 'calcium switch' conflict with one study showing that PC1 precedes desmoplakin and another showing that it follows desmoplakin (Scheffers et al, 2000;Silberberg et al, 2005).…”