Disease relevance of Nedd4a

• Our results demonstrate that Nedd4 is a negative regulator of ENaC and suggest that the loss of Nedd4 binding sites in ENaC observed in Liddle's syndrome may explain the increase in channel number at the cell surface, increased Na+ reabsorption by the distal nephron, and hence the hypertension [1].

High impact information on Nedd4a

• Here, we investigate, using the Xenopus oocyte system, whether Nedd4 affects ENaC function [1].
• Nedd4 is a ubiquitin protein ligase composed of a C2 domain, three (or four) WW domains and a ubiquitin ligase Hect domain [2].
• It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4 [3].
• Effects of the above phosphorylations on interactions between ENaC and Nedd4 have been studied using surface plasmon resonance [3].
• In the present study we examined whether CFTR interacts with ENaC by interfering with the Nedd4- and ubiquitin-mediated endocytosis of ENaC [4].

Biological context of Nedd4a

• A point mutation in the beta-subunit known to impair regulation of the channel by Nedd4 (Y618A) had no significant effect on the response to sgk [5].

Anatomical context of Nedd4a

• The C2 domain of the ubiquitin protein ligase Nedd4 mediates Ca2+-dependent plasma membrane localization [6].
• The C2 domain of Nedd4, expressed as a glutathione S-transferase (GST) fusion protein, was sufficient to bind cellular membranes in a Ca2+-dependent manner [6].
• These results indicate that the putative C2 domain of Nedd4 acts as a bona fide C2 domain which binds phospholipids and membranes in a Ca2+-dependent fashion and is involved in localizing the protein primarily to the apical region of polarized epithelial cells in response to Ca2+ [6].
• The effect of Nedd4 was not observed in the PY motif mutated channel or in the skeletal muscle voltage-gated Na+ channel, which lacks a PY motif [7].

Associations of Nedd4a with chemical compounds

• Here we show that Nedd4, endogenously expressed in Madin-Darby canine kidney cells, was redistributed from the cytosolic to the particulate fraction in response to ionomycin plus Ca2+ treatment [6].
• Whilst the alphaENaC and Nedd4 genes showed no significant response to either steroid, both the beta- and gammaENaC mRNA levels were increased acutely by both aldosterone and dexamethasone [8].

Physical interactions of Nedd4a

• We have recently identified the ubiquitin-protein ligase Nedd4 as an interacting protein with ENaC and demonstrated that Nedd4 binds by its WW domains to the proline-rich PY motifs of ENaC [9].

Other interactions of Nedd4a

• Interactions of beta and gamma ENaC with Nedd4 can be facilitated by an ERK-mediated phosphorylation [3].
• Expression of genes encoding components of the ubiquitin-proteasome pathway of protein degradation were elevated with HS, including ubiquitin, MAFbx, Murf-1, Nedd4, and XIAP, and proteasome subunits C2 and C9 [10].
• We have recently demonstrated an association between the WW domains of Nedd4 and the proline-rich PY motifs (XPPXY) of the epithelial Na+ channel, as well as with PY motifs of several other proteins [6].

Analytical, diagnostic and therapeutic context of Nedd4a

• A similar treatment of polarized Madin-Darby canine kidney cells led to an apical and lateral membrane localization of Nedd4, as determined by immunostaining and confocal microscopy [6].

References