title: Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.
abstract: Mutations in with-no-lysine (K) kinase 4 (WNK4) and a ubiquitin E3 ligase complex component kelch-like 3 (KLHL3) both cause pseudohypoaldosteronism II (PHAII), a hereditary form of hypertension. We determined whether WNK4 or its effector is regulated by KLHL3 in Xenopus oocytes. KLHL3 inhibited the positive effect of WNK4 on Na(+)-Cl(-) cotransporter (NCC) by decreasing WNK4 protein abundance without decreasing that of NCC and the downstream kinase OSR1 directly. Ubiquitination and degradation of WNK4 were induced by KLHL3. The effect of KLHL3 on WNK4 degradation was blocked by a dominant negative form of cullin 3. All five PHAII mutations of KLHL3 tested disrupted the regulation on WNK4. We conclude that KLHL3 is a substrate adaptor for WNK4 in a ubiquitin E3 ligase complex.
authors.affiliation: Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0006, USA.
authors.forename: Guojin
authors.initials: G
authors.lastname: Wu
authors.forename: Ji-Bin
authors.initials: JB
authors.lastname: Peng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D044842:Cullin Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis; D011546:Pseudohypoaldosteronism / Q000235:genetics*; D011955:Receptors, Drug / Q000378:metabolism; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C503645:CUL3 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C489837:KLHL3 protein, human; D008840:Microfilament Proteins; D011955:Receptors, Drug; C578875:Slc12a3 protein, mouse; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; C433806:WNK4 protein, human