Figure 1.

Model of ENaC maturation and regulation by NEDD4-2. Immature ENaC subunits undergo processing to mature forms by proteolytic cleavage and glycosylation (purple dots: processed N-glycans). Under high cytosolic Na⁺ conditions, PPxY (PY) motifs on ENaC subunits bind to WW domains of NEDD4-2. This results in ubiquitination of ENaC and subsequent removal from the membrane. In Nedd4-2 KO mice, mature ENaC is retained on the membrane leading to increased Na⁺ reabsorption and ultimately resulting in hypertension and kidney disease.