Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation

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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
08:55

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

Guojin Wu1, Ji-Bin Peng

  • 1Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0006, USA.

FEBS Letters
|May 14, 2013
PubMed

Insights

Kelch-like 3 (KLHL3) targets with-no-lysine (K) kinase 4 (WNK4) for degradation, explaining its role in pseudohypoaldosteronism II (PHAII) hypertension. This discovery clarifies KLHL3

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Nephrology

Background:

  • Mutations in WNK4 and KLHL3 cause pseudohypoaldosteronism II (PHAII), a hereditary hypertension.
  • The precise molecular mechanism linking KLHL3 to WNK4 in PHAII pathogenesis remains unclear.

Purpose of the Study:

  • To investigate whether KLHL3 regulates WNK4 and its downstream targets.
  • To elucidate the role of KLHL3 in the ubiquitination and degradation of WNK4.

Main Methods:

  • Experiments were conducted using Xenopus oocytes.
  • WNK4 protein abundance, NCC activity, and OSR1 levels were assessed.
  • Ubiquitination assays and dominant-negative cullin 3 inhibition were employed.

Main Results:

  • KLHL3 inhibited WNK4's positive effect on the Na(+)-Cl(-) cotransporter (NCC).
  • KLHL3 decreased WNK4 protein levels without affecting NCC or OSR1 directly.
  • KLHL3-induced WNK4 ubiquitination and degradation, which was blocked by dominant-negative cullin 3.
  • All tested PHAII mutations in KLHL3 impaired WNK4 regulation.

Conclusions:

  • KLHL3 acts as a substrate adaptor for WNK4 within a ubiquitin E3 ligase complex.
  • This interaction mediates WNK4 degradation, contributing to PHAII pathogenesis.
  • Understanding this pathway offers insights into hypertension mechanisms.

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