title: Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel.
abstract: The epithelial Na(+) channel (ENaC) is a critical component of the pathway maintaining salt and water balance. The channel is regulated by members of the Nedd4 family of ubiquitin-protein ligases, which bind to channel subunits and catalyze channel internalization and degradation. ENaC mutations that abolish this interaction cause Liddle's syndrome, a genetic form of hypertension. Here, we test the hypothesis that WW domain-containing protein 2 (WWP2), a member of the Nedd4 family of ubiquitin-protein ligases, is a candidate to regulate ENaC. Consistent with this hypothesis, we found that WWP2 is expressed in epithelial tissues that express ENaC, as well as in a wide variety of other tissues. WWP2 contains four WW domains, three of which bound differentially to ENaC subunits. In contrast, all four human Nedd4-2 WW domains bound to ENaC. WWP2 inhibited ENaC when coexpressed in epithelia, requiring a direct interaction between the proteins; mutation of the ENaC PY motifs abolished inhibition. Thus expression, binding, and functional data all suggest that WWP2 is a candidate to regulate ENaC-mediated Na(+) transport in epithelia.
authors.affiliation: Department of Physiology, University of Otago, Dunedin 9100, New Zealand. fiona.mcdonald@stonebow.otago.ac.nz
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: McDonald
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Western
authors.forename: John D
authors.initials: JD
authors.lastname: McNeil
authors.forename: Brittany C
authors.initials: BC
authors.lastname: Thomas
authors.forename: Diane R
authors.initials: DR
authors.lastname: Olson
authors.forename: Peter M
authors.initials: PM
authors.lastname: Snyder
mesh_terms: D000818:Animals; D001665:Binding Sites; D015152:Blotting, Northern; D002135:Calcium-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004553:Electric Conductivity; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D004848:Epithelium / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008025:Ligases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016296:Mutagenesis; D000075702:Nedd4 Ubiquitin Protein Ligases; D016133:Polymerase Chain Reaction; D051381:Rats; D011993:Recombinant Fusion Proteins; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D013961:Thyroid Gland / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection; D044767:Ubiquitin-Protein Ligases
chemical_list: D002135:Calcium-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D011993:Recombinant Fusion Proteins; D015222:Sodium Channels; D012964:Sodium; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618484:Nedd4 protein, rat; C000618485:Nedd4L protein, human; C465283:WWP2 protein, human; D044767:Ubiquitin-Protein Ligases; D008025:Ligases