Article (Scientific journals)
CLC-5 and KIF3B interact to facilitate CLC-5 plasma membrane expression, endocytosis, and microtubular transport: relevance to pathophysiology of Dent's disease.
Reed, Anita A. C.; Loh, Nellie Y.; Terryn, Sara et al.
2010In American Journal of Physiology. Renal, Fluid and Electrolyte Physiology, 298 (2), p. 365-80
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Keywords :
Adult; Albumins/metabolism; Animals; COS Cells; Cell Line; Cercopithecus aethiops; Chloride Channels/metabolism/physiology; DNA, Complementary; Down-Regulation; Drug Interactions; Electric Conductivity; Endocytosis/physiology; Gene Library; Genetic Diseases, X-Linked/physiopathology; Humans; Kidney/cytology/metabolism; Kidney Diseases/physiopathology; Kidney Tubules, Proximal/cytology/metabolism; Kinesin/metabolism; Mice; Mice, Knockout; Microtubules/metabolism; Protein Interaction Domains and Motifs; Protein Transport; Two-Hybrid System Techniques; Up-Regulation
Abstract :
[en] Renal tubular reabsorption is important for extracellular fluid homeostasis and much of this occurs via the receptor-mediated endocytic pathway. This pathway is disrupted in Dent's disease, an X-linked renal tubular disorder that is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. Dent's disease is due to mutations of CLC-5, a chloride/proton antiporter, expressed in endosomes and apical membranes of renal tubules. Loss of CLC-5 function alters receptor-mediated endocytosis and trafficking of megalin and cubilin, although the underlying mechanisms remain to be elucidated. Here, we report that CLC-5 interacts with kinesin family member 3B (KIF3B), a heterotrimeric motor protein that facilitates fast anterograde translocation of membranous organelles. Using yeast two-hybrid, glutathione-S-transferase pull-down and coimmunoprecipitation assays, the COOH terminus of CLC-5 and the coiled-coil and globular domains of KIF3B were shown to interact. This was confirmed in vivo by endogenous coimmunoprecipitation of CLC-5 and KIF3B and codistribution with endosomal markers in mouse kidney fractions. Confocal live cell imaging in kidney cells further demonstrated association of CLC-5 and KIF3B, and transport of CLC-5-containing vesicles along KIF3B microtubules. KIF3B overexpression and underexpression, using siRNA, had reciprocal effects on whole cell chloride current amplitudes, CLC-5 cell surface expression, and endocytosis of albumin and transferrin. Clcn5(Y/-) mouse kidneys and isolated proximal tubular polarized cells showed increased KIF3B expression, whose effects on albumin endocytosis were dependent on CLC-5 expression. Thus, the CLC-5 and KIF3B interaction is important for CLC-5 plasma membrane expression and for facilitating endocytosis and microtubular transport in the kidney.
Disciplines :
Genetics & genetic processes
Author, co-author :
Reed, Anita A. C.
Loh, Nellie Y.
Terryn, Sara
Lippiat, Jonathan D.
Partridge, Chris
Galvanovskis, Juris
Williams, Sian E.
JOURET, François  ;  Centre Hospitalier Universitaire de Liège - CHU > Néphrologie
Wu, Fiona T. F.
Courtoy, Pierre J.
Nesbit, M. Andrew
Rorsman, Patrik
Devuyst, Olivier
Ashcroft, Frances M.
Thakker, Rajesh V.
More authors (5 more) Less
Language :
English
Title :
CLC-5 and KIF3B interact to facilitate CLC-5 plasma membrane expression, endocytosis, and microtubular transport: relevance to pathophysiology of Dent's disease.
Publication date :
2010
Journal title :
American Journal of Physiology. Renal, Fluid and Electrolyte Physiology
ISSN :
0363-6127
eISSN :
2161-1157
Publisher :
American Physiological Society, United States - Maryland
Volume :
298
Issue :
2
Pages :
F365-80
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
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