14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase

J Biol Chem. 2005 Apr 1;280(13):13187-94. doi: 10.1074/jbc.M412884200. Epub 2005 Jan 26.


The ubiquitin E3 protein ligase Nedd4-2 is a physiological regulator of the epithelial sodium channel ENaC, which is essential for transepithelial Na+ transport and is linked to Liddle's syndrome, an autosomal dominant disorder of human salt-sensitive hypertension. Nedd4-2 function is negatively regulated by phosphorylation via a serum- and glucocorticoid-inducible protein kinase (Sgk1), which serves as a mechanism to inhibit the ubiquitination-dependent degradation of ENaC. We report here that 14-3-3 proteins participate in this regulatory process through a direct interaction with a phosphorylated form of human Nedd4-2 (a human gene product of KIAA0439, termed hNedd4-2). The interaction is dependent on Sgk1-catalyzed phosphorylation of hNedd4-2 at Ser-468. We found that this interaction preserved the activity of the Sgk1-stimulated ENaC-dependent Na+ current while disrupting the interaction decreased ENaC density on the Xenopus laevis oocytes surface possibly by enhancing Nedd4-2-mediated ubiquitination that leads to ENaC degradation. Our findings suggest that 14-3-3 proteins modulate the cell surface density of ENaC cooperatively with Sgk1 kinase by maintaining hNedd4-2 in an inactive phosphorylated state.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism
  • 14-3-3 Proteins / physiology*
  • Animals
  • Catalysis
  • Cattle
  • Cell Line
  • Cell Membrane / metabolism
  • Electrophoresis, Polyacrylamide Gel
  • Electrophysiology
  • Endosomal Sorting Complexes Required for Transport
  • Epithelial Sodium Channels
  • Genes, Dominant
  • Glutathione Transferase / metabolism
  • Humans
  • Immediate-Early Proteins
  • Nedd4 Ubiquitin Protein Ligases
  • Nuclear Proteins / metabolism
  • Oocytes / metabolism
  • PC12 Cells
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphorylation
  • Plasmids / metabolism
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Serine / chemistry
  • Silver Staining
  • Sodium / metabolism
  • Sodium Channels / chemistry*
  • Time Factors
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism*
  • Xenopus
  • Xenopus Proteins
  • Xenopus laevis


  • 14-3-3 Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Epithelial Sodium Channels
  • Immediate-Early Proteins
  • Nuclear Proteins
  • Sodium Channels
  • Ubiquitin
  • Xenopus Proteins
  • Serine
  • Sodium
  • NEDD4L protein, rat
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, Xenopus
  • Nedd4 protein, human
  • Nedd4 protein, rat
  • Nedd4L protein, human
  • nedd4l protein, Xenopus
  • Ubiquitin-Protein Ligases
  • Glutathione Transferase
  • Protein Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • Phosphoric Monoester Hydrolases