Physiological Functions of Nedd4-2: Lessons from Knockout Mouse Models

Protein modification by ubiquitination plays a key evolutionarily conserved role in regulating membrane proteins. Nedd4-2, a ubiquitin ligase, targets membrane proteins such as ion channels and transporters for ubiquitination. This Nedd4-2-mediated ubiquitination provides a crucial step in controlling the membrane availability of these proteins, thus affecting their signaling and physiological outcomes. In one well-studied example, Nedd4-2 fine-tunes the physiological function of the epithelial sodium channel (ENaC), thus modulating Na+ reabsorption by epithelia to maintain whole-body Na+ homeostasis. This review summarizes the key signaling pathways regulated by Nedd4-2 and the possible implications of such regulation in various pathologies.