Figure 1

Regulation of ENaC by Nedd4-2 in homeostasis. The ubiquitin ligase Nedd4-2 binds (via its WW domains) to the PY motifs of ENaC, in turn ubiquitylating and targeting ENaC for endocytosis and lysosomal degradation. This process can be inhibited by Sgk1- or Akt-mediated phosphorylation of Nedd4-2, which leads to binding of 14-3-3 proteins to phosphorylated Nedd4-2, thus preventing Nedd4-2 from associating with ENaC and thus increasing ENaC levels at the plasma membrane. Sgk1 can also upregulate ENaC independently of Nedd4-2.