Role of the UPS in Liddle syndrome

Abstract

Hypertension is a serious medical problem affecting a large population worldwide. Liddle syndrome is a hereditary form of early onset hypertension caused by mutations in the epithelial Na+ channel (ENaC). The mutated region, called the PY (Pro-Pro-x-Tyr) motif, serves as a binding site for Nedd4-2, an E3 ubiquitin ligase from the HECT family. Nedd4-2 binds the ENaC PY motif via its WW domains, normally leading to ENaC ubiquitylation and endocytosis, reducing the number of active channels at the plasma membrane. In Liddle syndrome, this endocytosis is impaired due to the inability of the mutated PY motif in ENaC to properly bind Nedd4-2. This leads to accumulation of active channels at the cell surface and increased Na+ (and fluid) absorption in the distal nephron, resulting in elevated blood volume and blood pressure. Small molecules/compounds that destabilize cell surface ENaC, or enhance Nedd4-2 activity in the kidney, could potentially serve to alleviate hypertension. PUBLICATION HISTORY : Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).

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.

Figure 2

Regulation of ENaC by Nedd4-2 and its impairment in Liddle syndrome. In Liddle syndrome, deletion/mutation of the PY motif in βENaC (or γENaC, not shown) impairs the ability of Nedd4-2 to bind (and thus ubiquitylate) ENaC, leading to accumulation of ENaC channels at the plasma membrane and increased channel activity. (Modified with permission from Staub and Rotin).