Research progress of Nedd4L in cardiovascular diseases

Figures

• 

  Fig. 1. The mechanism diagrams of how SGK1 regulates sodium reabsorption by Nedd4L. A Epithelial sodium channel (ENaC) can be degraded by Neuronal precursor cell expression developmentally downregulated 4-like (Nedd4L) to maintain sodium balance. B Serum and glucocorticoid-regulated kinase 1(SGK1) phosphorylates and inhibits Nedd4L which is an ubiquitin ligase, thereby failing to reduce the channel expression and stimulate ion channel degradation. The phosphorylation (mainly surrounding amino acids Ser444, Ser338) mediated by SGK1 induces the interaction of Nedd4L with members of the 14-3-3 protein family, which in turn disrupts the ubiquitination and degradation of ENaC by Nedd4L, ultimately leading to more sodium reabsorption.

• 

  Fig. 2. The molecular mechanism of the differences between the normal and liddle syndrome. Neuronal precursor cell expression developmentally downregulated 4-like(Nedd4L) is composed of C2 domain, four WW domains and HECT domain. α, β, and γ subunits of ENaC contains a conserved proline-tyrosine (PY) motif at the C-terminus which is also the binding site for the ubiquitin ligase Nedd4L. After mutation in this PY motif happens, the binding capacity to the WW domain of Nedd4L will decrease; thereby accelerate the cell activity and expression of ENaC, leading to its uncapable of degradation. Ultimately, increase the absorption of sodium ion in the distal nephron.