Regulation of the epithelial sodium channel by N4WBP5A, a novel Nedd4/Nedd4-2-interacting protein.
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 that is believed to be important for interaction with the WW domains of the ubiquitin-protein ligases, Nedd4 and Nedd4-2. 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 shown to result in increased ENaC activity and arterial hypertension. Here we present evidence that N4WBP5A, a novel Nedd4/Nedd4-2-binding protein, is a potential regulator of ENaC. In Xenopus laevis oocytes N4WBP5A increases surface expression of ENaC by reducing the rate of ENaC retrieval. We further demonstrate that N4WBP5A prevents sodium feedback inhibition of ENaC possibly by interfering with the xNedd4-2-mediated regulation of ENaC. As N4WBP5A binds Nedd4/Nedd4-2 via PPXY motif/WW domain interactions and appears to be associated with specific intracellular vesicles, we propose that N4WBP5A functions by regulating Nedd4/Nedd4-2 availability and trafficking. Because N4WBP5A is highly expressed in native renal collecting duct and other tissues that express ENaC, it is a likely candidate to modulate ENaC function in vivo.
Konstas
Angelos-Aristeidis
AA
University Laboratory of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom.
Shearwin-Whyatt
Linda M
LM
Fotia
Andrew B
AB
Degger
Brian
B
Riccardi
Daniela
D
Cook
David I
DI
Korbmacher
Christoph
C
Kumar
Sharad
S
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D053143:Caspase 2; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D006801:Humans; D008025:Ligases / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D000075702:Nedd4 Ubiquitin Protein Ligases; D009865:Oocytes / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases; D029867:Xenopus Proteins; D014982:Xenopus laevis
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D008565:Membrane Proteins; C451223:NDFIP1 protein, human; D015222:Sodium Channels; D029867:Xenopus Proteins; D012964:Sodium; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618482:Nedd4 protein, Xenopus; C000618483:Nedd4 protein, human; C000618484:Nedd4 protein, rat; C000618485:Nedd4L protein, human; C000618460:nedd4l protein, Xenopus; D044767:Ubiquitin-Protein Ligases; C490360:CASP2 protein, human; C490359:Casp2 protein, rat; D053143:Caspase 2; D003546:Cysteine Endopeptidases; D008025:Ligases