CUL3KLHL3

CUL3KLHL3 refers to the E3 ubiquitin ligase complex formed by Cullin-3 (CUL3) and the Kelch-like protein KLHL3, a member of the Cullin-RING ligase (CRL) family. In these complexes, CUL3 serves as the scaffold that organizes the core ligase together with RBX1 and the associated substrate adaptor, while KLHL3 provides the substrate-binding interface, recognizing specific target proteins for ubiquitination. The activity of CRL3 ligases generally requires neddylation of CUL3 to enable ubiquitin transfer to substrates.

The best-characterized substrates of the CUL3KLHL3 complex are WNK kinases, particularly WNK1 and WNK4. KLHL3 binds these kinases via its Kelch repeats, promoting their ubiquitination and proteasomal degradation. Through this regulatory axis, CUL3KLHL3 modulates the WNK-SPAK/OSR1 signaling pathway, which controls the activity of the sodium-choloride cotransporter NCC in the kidney. By restraining WNK levels, the complex helps maintain electrolyte balance and normal blood pressure.

Genetic disruption of either CUL3 or KLHL3 can lead to familial hyperkalemic hypertension (FHHt), also known as Gordon syndrome. Patients with pathogenic variants exhibit dysregulated WNK signaling, resulting in increased NCC activity, hypertension, hyperkalemia, and metabolic acidosis. The condition highlights the physiological role of the CUL3KLHL3 complex in renal ion transport and cardiovascular regulation. Research into this complex continues to elucidate substrate specificity, structural interactions, and potential therapeutic approaches for related hypertensive disorders.