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Title

Cyclophilin B interacts with sodium-potassium ATPase and is required for pump activity in proximal tubule cells of the kidney

Authors
Sune, Guillermo
Sarro, Eduard
Puigmule, Marta
Lopez-Hellin, Joan
Meseguer, Anna
Published in PLOS ONE. 2010, vol. 5, no. 11, p. e13930
Abstract Cyclophilins (Cyps), the intracellular receptors for Cyclosporine A (CsA), are responsible for peptidyl-prolyl cis-trans isomerisation and for chaperoning several membrane proteins. Those functions are inhibited upon CsA binding. Albeit its great benefits as immunosuppressant, the use of CsA has been limited by undesirable nephrotoxic effects, including sodium retention, hypertension, hyperkalemia, interstial fibrosis and progressive renal failure in transplant recipients. In this report, we focused on the identification of novel CypB-interacting proteins to understand the role of CypB in kidney function and, in turn, to gain further insight into the molecular mechanisms of CsA-induced toxicity. By means of yeast two-hybrid screens with human kidney cDNA, we discovered a novel interaction between CypB and the membrane Na/K-ATPase beta1 subunit protein (Na/K-beta1) that was confirmed by pull-down, co-immunoprecipitation and confocal microscopy, in proximal tubule-derived HK-2 cells. The Na/K-ATPase pump, a key plasma membrane transporter, is responsible for maintenance of electrical Na+ and K+ gradients across the membrane. We showed that CypB silencing produced similar effects on Na/K-ATPase activity than CsA treatment in HK-2 cells. It was also observed an enrichment of both alpha and beta subunits in the ER, what suggested a possible failure on the maturation and routing of the pump from this compartment towards the plasma membrane. These data indicate that CypB through its interaction with Na/K-beta1 might regulate maturation and trafficking of the pump through the secretory pathway, offering new insights into the relationship between cyclophilins and the nephrotoxic effects of CsA.
Keywords AnimalsBlotting, WesternCOS CellsCell Line, TransformedCercopithecus aethiopsCyclophilins/genetics/*metabolismCyclosporine/pharmacologyEnzyme Inhibitors/pharmacologyHEK293 CellsHumansKidney Tubules, Proximal/cytology/*metabolismProtein Binding/drug effectsProtein Subunits/genetics/metabolismRNA InterferenceReverse Transcriptase Polymerase Chain ReactionSodium-Potassium-Exchanging ATPase/genetics/*metabolismTwo-Hybrid System Techniques
Identifiers
PMID: 21085665
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Research group Réplication virale, pathogénèse et immunité (848)
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(ISO format)
SUNE, Guillermo et al. Cyclophilin B interacts with sodium-potassium ATPase and is required for pump activity in proximal tubule cells of the kidney. In: PLOS ONE, 2010, vol. 5, n° 11, p. e13930. https://archive-ouverte.unige.ch/unige:20663

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Deposited on : 2012-05-22

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