Kelch-like protein 3

Kelch-like protein 3 (KLHL3) is a substrate adaptor of the BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates ion transport in the kidney's distal nephron. It mediates ubiquitination and degradation of WNK kinases and other transport-related proteins, thereby controlling sodium-chloride reabsorption and electrolyte homeostasis (UniProt: Q9UH77). KLHL3 is primarily characterized by its role in renal physiology, and variants in KLHL3 are associated with pseudohypoaldosteronism 2D (PHA2D), a monogenic hypertensive disorder (UniProt: Q9UH77).

KLHL3 is downregulated in Alzheimer's disease brain tissue. In a post-mortem AD versus age-matched control comparison using quantitative proteomics, KLHL3 showed a mean log2 fold-change of −0.776 across examined subcellular fractions (Chaparral AD proteomics). The functional significance of this reduction in AD neuropathology remains to be determined, though altered ion homeostasis and ubiquitin-proteasome function are emerging themes in neurodegeneration.