The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel.
The amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in fluid and electrolyte homeostasis and consists of alpha, beta, and gamma 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 beta or gamma 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.
Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science, Frome Road, Adelaide, South Australia 5000, Australia.
K F
KF
Harvey
A
A
Dinudom
D I
DI
Cook
S
S
Kumar
D000818:Animals; D002135:Calcium-Binding Proteins / Q000502:physiology; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D008025:Ligases / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D021122:Protein Subunits; D012333:RNA, Messenger / Q000032:analysis; D012964:Sodium / Q000494:pharmacology; D015222:Sodium Channels / Q000737:chemistry / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
D002135:Calcium-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D021122:Protein Subunits; D012333:RNA, Messenger; D015222:Sodium Channels; D012964:Sodium; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D008025:Ligases