Insights in cullin 3/WNK4 and its relationship to blood pressure regulation and electrolyte homeostasis

Cell Signal. 2014 Jun;26(6):1166-72. doi: 10.1016/j.cellsig.2014.01.032. Epub 2014 Feb 8.


One of the most important systems for protein degradation is the ubiquitin-proteasome system (UPS). The highly specific process called ubiquitination is provided by the E3 ubiquitin ligases, which mediates degradation via the proteasome system. The ubiquitin ligases based on cullins are the type of ubiquitin ligases known so far. The complex based on cullin 3 (Cul3) requires that its target protein has a bric-a-brac/tram-track/broad-complex (BTB) domain to recognize it. Cul3 has been widely associated with Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) and the cytoprotective nuclear factor erythroid 2 related factor 2 (Nrf2) pathway and the proper control of cell cycle progression. Recently, Cul3 has been linked to the development of type II pseudohypoaldosteronism (PHAII or Gordon's syndrome) due to the fact that Cul3 has the ability to bind to Kelch-like 3 protein (KLHL3) and therefore mediating the degradation of some members of the WNK kinases. In this work we focused on highlighting how Cul3 system is involved in the regulation of electrolyte homeostasis and blood pressure.

Keywords: Cullin 3; Hypertension; KLHL3; Ubiquitin–proteasome system; WNK kinases.

Publication types

  • Review

MeSH terms

  • Blood Pressure*
  • Cullin Proteins / physiology*
  • Homeostasis
  • Humans
  • Kidney / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Proteolysis
  • Ubiquitination
  • Water-Electrolyte Balance*


  • CUL3 protein, human
  • Cullin Proteins
  • Protein-Serine-Threonine Kinases
  • WNK4 protein, human
  • Proteasome Endopeptidase Complex