Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice.

ABSTRACT:

Background

Mutations in the ubiquitin ligase scaffold protein Cullin 3 (CUL3) gene cause the disease familial hyperkalemic hypertension (FHHt). In the kidney, mutant CUL3 (CUL3-Δ9) increases abundance of With-No-Lysine (K) Kinase 4 (WNK4), inappropriately activating sterile 20/SPS-1-related proline/alanine-rich kinase (SPAK), which then phosphorylates and hyperactivates the Na⁺Cl^- cotransporter (NCC). The precise mechanism by which CUL3-Δ9 causes FHHt is unclear. We tested the hypothesis that reduced abundance of CUL3 and of Kelch-like 3 (KLHL3), the CUL3 substrate adaptor for WNK4, is mechanistically important. Because JAB1, an enzyme that inhibits CUL3 activity by removing the ubiquitin-like protein NEDD8, cannot interact with CUL

SUBMITTER: Maeoka Y 

PROVIDER: S-EPMC8975056 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature