The Nedd4-like Protein KIAA0439 Is a Potential Regulator of the Epithelial Sodium Channel

• Published in: The Journal of biological chemistry Vol. 276; no. 11; pp. 8597 - 8601
• Main Authors: Harvey, Kieran F., Dinudom, Anuwat, Cook, David I., Kumar, Sharad
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-03-2001; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Calcium-Binding Proteins - physiology; Endosomal Sorting Complexes Required for Transport; Epithelial Sodium Channels; Ligases - genetics; Ligases - physiology; Male; Mice; Nedd4 Ubiquitin Protein Ligases; Protein Subunits; RNA, Messenger - analysis; Sodium - pharmacology; Sodium Channels - chemistry; Sodium Channels - physiology; Ubiquitin-Protein Ligases
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C000906200

The amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in fluid and electrolyte homeostasis and consists of α, β, and γ subunits. The carboxyl terminus of each ENaC subunit contains a PPxY, motif which is believed to be important for interaction with the WW domains of the ubiquitin-protein ligase, Nedd4. Disruption of this interaction, as in Liddle's syndrome, where mutations delete or alter the PPxY motif of either the β or γ subunits, has been proposed to result in increased ENaC activity. Here we present evidence that KIAA0439 protein, a close relative of Nedd4, is also a potential regulator of ENaC. We demonstrate that KIAA0439 WW domains bind all three ENaC subunits. We show that a recombinant KIAA0439 WW domain protein acts as a dominant negative mutant that can interfere with the Na+-dependent feedback inhibition of ENaC in whole-cell patch clamp experiments. We propose that KIAA0439 and Nedd4 proteins either play a redundant role in ENaC regulation or function in a tissue- and/or signal-specific manner to down-regulate ENaC.