A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel

Liddle's syndrome is a form of inherited hypertension linked to mutations i n the genes encoding the epithelial Na+ channel (ENaC). These mutations alt er or delete PY motifs involved in protein-protein interactions with a ubiq uitin-protein ligase, Nedd4. Here we show that Na+ transporting cells, deri ved from mouse cortical collecting duct, express two Nedd4 proteins with di fferent structural organization and characteristics of ENaC regulation: 1) the classical Nedd4 therein referred to as Nedd4-1) containing one amino-te rminal C2, three WW, and one HECT-ubiquitin protein ligase domain and 2) a novel Nedd4 protein (Nedd4-2), homologous to Xenopus Nedd4 and comprising f our WW, one HECT, yet lacking a C2 domain, Nedd4-2, but not Nedd4-1, inhibi ts ENaC activity when coexpressed in Xenopus oocytes and this property corr elates with the ability to bind to ENaC, as only Nedd4-2 coimmunoprecipitat es with ENaC. Furthermore, this interaction depends on the presence of at l east one PY motif in the ENaC complex and on WW domains 3 and 4 in Nedd4-2, Thus, these results suggest that the novel suppressor protein Nedd4-2 is t he regulator of ENaC and hence a potential susceptibility gene for arterial hypertension.