Abstract
Nedd4-2 is a ubiquitin ligase previously demonstrated to regulate endocytosis and lysosomal degradation of the epithelial Na+ channel (ENaC) and other ion channels and transporters. Recent studies using Nedd4-2 knockout mice specifically in kidney or lung epithelia has revealed a critical role for this E3 ubiquitin ligase in regulating salt and fluid transport in these tissues/organs and in maintaining homeostasis of body blood pressure. Interestingly, the primary targets for Nedd4-2 may differ in these two organs: in the lung Nedd4-2 targets ENaC, and loss of Nedd4-2 leads to excessive ENaC function and to cystic fibrosis – like lung disease, whereas in the kidney, Nedd4-2 targets the Na+/Cl− cotransporter (NCC) in addition to targeting ENaC. In accord, loss of Nedd4-2 in the distal nephron leads to increased NCC abundance and function. The aldosterone-responsive kinase, Sgk1, appears to be involved in the regulation of NCC by Nedd4-2 in the kidney, similar to its regulation of ENaC. Collectively, these new findings underscore the physiological importance of Nedd4-2 in regulating epithelial salt and fluid transport and balance.
Highlights
Neuronal precursor cell expressed developmentally downregulated 4 (Nedd4) proteins are E3 ubiquitin ligases that belong to the HECT family
SUMMARY/PERSPECTIVE Recent knockout studies of Nedd4-2 in both the distal nephron and in lung epithelia have helped cement our understanding of the suppressive role of Nedd4-2 on epithelial Na+ channel (ENaC), which was extensively studied earlier using cultured cells and Xenopus oocytes
These in vivo knockout studies have uncovered a new unsuspected role for Nedd4-2 in suppressing NCC in the kidney. These animal model studies have important implications to our understanding of human diseases, since total loss of Nedd4-2 leads to salt-induced hypertension, and its specific loss in lung epithelia results in CF-like lung disease
Summary
Neuronal precursor cell expressed developmentally downregulated 4 (Nedd4) proteins are E3 ubiquitin ligases that belong to the HECT family. SUMMARY/PERSPECTIVE Recent knockout studies of Nedd4-2 in both the distal nephron and in lung epithelia have helped cement our understanding of the suppressive role of Nedd4-2 on ENaC, which was extensively studied earlier using cultured cells and Xenopus oocytes.
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