Hsp70 promotes epithelial sodium channel functional expression by increasing its association with coat complex II and its exit from endoplasmic reticulum

Rebecca A. Chanoux, Amal Robay, Calla B. Shubin, Catherine Kebler, Laurence Suaud, Ronald C. Rubenstein

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The epithelial sodium channel (ENaC) plays an important role in the homeostasis of blood pressure and of the airway surface liquid, and inappropriate regulation of ENaC results in refractory hypertension (in Liddle syndrome) and impaired mucociliary clearance (in cystic fibrosis). The regulation of ENaC by molecular chaperones, such as the 70-kDa heat shock protein Hsp70, is not completely understood. Building on the previous suggestion by our group that Hsp70 promotes ENaC functional and surface expression in Xenopus oocytes, we investigated the mechanism by which Hsp70 acts upon ENaC in epithelial cells. In Madin-Darby canine kidney cells stably expressing epitope-tagged αβγ-ENaC and with tetracycline-inducible overexpression of Hsp70, treatment with 1 or 2mu;g/ml doxycycline increased total Hsp70 expression ~2-fold and ENaC functional expression ~1.4-fold. This increase in ENaC functionalexpressioncorrespondedtoanincreaseinENaCexpression at the apical surface of the cells and was not present when an ATPase-deficientHsp70wassimilarlyoverexpressed.Theincrease in functional expression was not due to a change in the rate at which ENaC was retrieved from the apical membrane. Instead, Hsp70 overexpression increased the association of ENaC with the Sec24D cargo recognition component of coat complex II, which carries protein cargo from the endoplasmic reticulum to the Golgi. These data support the hypothesis that Hsp70 promotes ENaC biogenesis and trafficking to the apical surface of epithelial cells.

Original languageEnglish
Pages (from-to)19255-19265
Number of pages11
JournalJournal of Biological Chemistry
Issue number23
Publication statusPublished - 1 Jun 2012
Externally publishedYes


ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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