Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia
| Autor: | Iris Hardege, Radoslav I. Enchev, Yasmin, Nicola T. Wood, Nichola Figg, Clare Johnson, S Cleary, James T Ferryman, Jinwei Zhang, Thimo Kurz, Keith Siew, Raya Al Maskari, Kevin M. O'Shaughnessy, Axel Knebel, Frances-Rose Schumacher |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
RBX1
Pseudohypoaldosteronism Cullin CUL3 Monogenic hypertension syndromes Proteasome Ubiquitin WNK/SPAK/OSR1 pathway cullin Protein Serine-Threonine Kinases medicine.disease_cause monogenic hypertension syndromes Mice ubiquitin medicine Animals Humans News & Views Research Articles Genetics Mice Knockout Mutation Protein-Serine-Threonine Kinases biology Cullin Proteins Intracellular Signaling Peptides and Proteins medicine.disease Phenotype Cell biology Familial hypertension Disease Models Animal HEK293 Cells proteasome biology.protein Molecular Medicine |
| Zdroj: | EMBO Molecular Medicine EMBO Molecular Medicine, 7 (10) |
| ISSN: | 1757-4684 1757-4676 |
| Popis: | Deletion of exon 9 from Cullin‐3 (CUL3, residues 403–459: CUL3Δ403–459) causes pseudohypoaldosteronism type IIE (PHA2E), a severe form of familial hyperkalaemia and hypertension (FHHt). CUL3 binds the RING protein RBX1 and various substrate adaptors to form Cullin‐RING‐ubiquitin‐ligase complexes. Bound to KLHL3, CUL3‐RBX1 ubiquitylates WNK kinases, promoting their ubiquitin‐mediated proteasomal degradation. Since WNK kinases activate Na/Cl co‐transporters to promote salt retention, CUL3 regulates blood pressure. Mutations in both KLHL3 and WNK kinases cause PHA2 by disrupting Cullin‐RING‐ligase formation. We report here that the PHA2E mutant, CUL3Δ403–459, is severely compromised in its ability to ubiquitylate WNKs, possibly due to altered structural flexibility. Instead, CUL3Δ403–459 auto‐ubiquitylates and loses interaction with two important Cullin regulators: the COP9‐signalosome and CAND1. A novel knock‐in mouse model of CUL3WT/Δ403–459 closely recapitulates the human PHA2E phenotype. These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models. These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases. EMBO Molecular Medicine, 7 (10) ISSN:1757-4676 ISSN:1757-4684 |
| Databáze: | OpenAIRE |
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