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© The Rockefeller University Press, 0021-9525/2000//111 $5.00
The Journal of Cell Biology, Volume 149, Number 1, , 2000 111-124

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

^a Integrated Graduate Program in the Life Sciences, Northwestern University Medical School, Chicago, Illinois 60611
^b Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611
^c Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana 46202
^d Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131
2325 Camino de Salud CRF 225, Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-5301.(505) 272-4193(505) 272-1459

wness{at}unm.edu

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.

Key Words: basolateral • adherens junction • epithelia • autosomal dominant polycystic kidney disease (ADPKD) • polycystin

© 2000 The Rockefeller University Press

Abbreviations used in this paper: ADPKD, autosomal dominant polycystic kidney disease; AEBSF, 4-(2-aminoethyl) benzenesulfonylfluoride, HCl; HA, hemagglutinin; HMEM, Hepes-buffered MEM; LDL-R, low density lipoprotein receptor; pAb, polyclonal antibody; PKD, polycystic kidney disease; SNARE, soluble N-ethylmaleimide–sensitive attachment protein receptor; TX, Triton X.

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