14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase.
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.
Mesh Terms:
14-3-3 Proteins, Animals, Catalysis, Cattle, Cell Line, Cell Membrane, Electrophoresis, Polyacrylamide Gel, Electrophysiology, Endosomal Sorting Complexes Required for Transport, Epithelial Sodium Channel, Genes, Dominant, Glutathione Transferase, Humans, Immediate-Early Proteins, Nuclear Proteins, Oocytes, PC12 Cells, Phosphoric Monoester Hydrolases, Phosphorylation, Plasmids, Protein Binding, Protein-Serine-Threonine Kinases, Rats, Serine, Silver Staining, Sodium, Sodium Channels, Time Factors, Ubiquitin, Ubiquitin-Protein Ligases, Xenopus, Xenopus laevis
14-3-3 Proteins, Animals, Catalysis, Cattle, Cell Line, Cell Membrane, Electrophoresis, Polyacrylamide Gel, Electrophysiology, Endosomal Sorting Complexes Required for Transport, Epithelial Sodium Channel, Genes, Dominant, Glutathione Transferase, Humans, Immediate-Early Proteins, Nuclear Proteins, Oocytes, PC12 Cells, Phosphoric Monoester Hydrolases, Phosphorylation, Plasmids, Protein Binding, Protein-Serine-Threonine Kinases, Rats, Serine, Silver Staining, Sodium, Sodium Channels, Time Factors, Ubiquitin, Ubiquitin-Protein Ligases, Xenopus, Xenopus laevis
J. Biol. Chem.
Date: Apr. 01, 2005
PubMed ID: 15677482
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