Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na+ channel cell surface expression

The epithelial Na + channel (ENaC) plays an essential role in the regulation of whole body Na + balance and blood pressure. The cell surface expression of this channel, a complex of three subunits (α, β and γENaC), has been shown to be regulated by hormones such as aldosterone and vasopressin and by intracellular signaling, including ubiquitylation and/or phosphorylation. However, the molecular mechanisms involving phosphorylation in the regulation of ENaC are unclear. Here we show by expression studies in Xenopus laevis oocytes that the aldosterone‐induced Sgk1 kinase interacts with the ubiquitin protein ligase Nedd4‐2 in a PY motif‐dependent manner and phosphorylates Nedd4‐2 on Ser444 and, to a lesser extent, Ser338. Such phosphorylation reduces the interaction between Nedd4‐2 and ENaC, leading to elevated ENaC cell surface expression. These data show that phosphorylation of an enzyme involved in the ubiquitylation cascade (Nedd4‐2) controls cell surface density of ENaC and propose a paradigm for the control of ion channels. Moreover, they suggest a novel and complete signaling cascade for aldosterone‐dependent regulation of ENaC.