KLHL3
Function
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron (PubMed:14528312, PubMed:22406640, PubMed:23387299, PubMed:23453970, PubMed:23576762, PubMed:23665031, PubMed:25313067, PubMed:35093948). The BCR(KLHL3) complex acts by mediating ubiquitination and degradation of WNK1 and WNK4, two activators of Na-Cl cotransporter SLC12A3/NCC in distal convoluted tubule cells of kidney, thereby regulating NaCl reabsorption (PubMed:23387299, PubMed:23453970, PubMed:23576762, PubMed:23665031, PubMed:25313067, PubMed:35093948). The BCR(KLHL3) complex also mediates ubiquitination and degradation of WNK3 (PubMed:35179207). The BCR(KLHL3) complex also mediates ubiquitination of CLDN8, a tight-junction protein required for paracellular chloride transport in the kidney, leading to its degradation (By similarity).
Involvement in disease
Pseudohypoaldosteronism 2D
PHA2D
A disorder characterized by severe hypertension, hyperkalemia, hyperchloremia, hyperchloremic metabolic acidosis, and correction of physiologic abnormalities by thiazide diuretics. PHA2D inheritance is autosomal dominant or recessive.
None
The disease is caused by variants affecting the gene represented in this entry.
Pathway
Protein modification; protein ubiquitination.
Post-translational modifications
Phosphorylation at Ser-433 by PKA or PKC decreases the interaction with WNK1 and WNK4, leading to inhibit their degradation by the BCR(KLHL3) complex (PubMed:25313067, PubMed:26435498, PubMed:27727489, PubMed:30718414). Phosphorylated at Ser-433 by PKC in response to angiotensin II signaling, decreasing ability to promote degradation of WNK1 and WNK4, leading to activation of Na-Cl cotransporter SLC12A3/NCC (PubMed:25313067). Phosphorylation at Ser-433 is increased by insulin (PubMed:26435498). Dephosphorylated at Ser-433 by calcineurin PPP3CA, promoting degradation of WNK1 and WNK4 (PubMed:30718414).
Sequence Similarities
Belongs to the KLHL3 family.
Tissue Specificity
Widely expressed.
Cellular localization
- Cytoplasm
- Cytosol
- Cytoplasm
- Cytoskeleton
Alternative names
KIAA1129, KLHL3, Kelch-like protein 3