Affinage

KLHL3

Kelch-like protein 3 · UniProt Q9UH77

Length
587 aa
Mass
65.0 kDa
Annotated
2026-04-28
45 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KLHL3 is a BTB-BACK-Kelch substrate adaptor that assembles with Cullin 3 to form a CRL3 E3 ubiquitin ligase controlling renal sodium balance and blood pressure by targeting WNK family kinases for proteasomal and autophagy-mediated degradation. The Kelch β-propeller domain recognizes a conserved acidic degron motif in WNK1–4, while the BTB-BACK domain mediates CUL3 binding and KLHL3 homodimerization; crystal structures of both interfaces define the molecular basis for disease-causing mutations (PMID:23573258, PMID:24641320, PMID:35179207). KLHL3-dependent ubiquitination of WNK4 suppresses the WNK–SPAK/OSR1–NCC phosphorylation cascade in the distal nephron, and loss-of-function KLHL3 mutations cause pseudohypoaldosteronism type II (familial hyperkalemic hypertension), as demonstrated by multiple knock-in and knockout mouse models (PMID:22406640, PMID:24821705, PMID:28052936). KLHL3 activity is regulated by phosphorylation at Ser433 by Akt, PKA, and PKC, which disrupts WNK binding, by COP9 signalosome–mediated CUL3 deneddylation that stabilizes KLHL3, and by O-GlcNAcylation; additional substrates include claudin-8 in the collecting duct and hnRNP Q1 during KSHV infection (PMID:26435498, PMID:30301860, PMID:25831548, PMID:35538151).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2012 High

    The genetic basis of familial hyperkalemic hypertension (PHAII) was unknown for many kindreds; whole-exome sequencing identified KLHL3 mutations as causative, establishing KLHL3 as a Cullin 3 substrate adaptor that regulates NCC-dependent sodium transport in the distal nephron.

    Evidence Linkage analysis and whole-exome sequencing in PHAII families with cell surface NCC expression assays

    PMID:22406640

    Open questions at the time
    • Substrate identity of the CRL3-KLHL3 complex was not yet known
    • Mechanism by which KLHL3 regulates NCC was indirect
  2. 2013 High

    The direct substrates and enzymatic activity of CRL3-KLHL3 were undefined; biochemical reconstitution and cell-based experiments demonstrated that KLHL3 binds WNK1 and WNK4, mediates their CUL3-dependent ubiquitination, and promotes their degradation — with PHAII mutations on either side disrupting the interaction.

    Evidence In vitro ubiquitylation assays, reciprocal Co-IP, siRNA knockdown, Xenopus oocyte reconstitution, WNK4 D561A knock-in mice

    PMID:23387299 PMID:23453970 PMID:23665031

    Open questions at the time
    • Structural basis of KLHL3-WNK recognition was not resolved
    • Relative contribution of WNK1 vs WNK4 degradation to PHAII pathogenesis was unclear
  3. 2013 High

    How PHAII mutations spanning different KLHL3 domains impair function was unknown; crystal structure of the BTB-BACK/CUL3 complex and domain-specific mutagenesis showed that BTB-BACK mutations disrupt CUL3 binding while Kelch mutations disrupt WNK binding, defining two distinct loss-of-function mechanisms.

    Evidence X-ray crystallography of KLHL3 BTB-BACK–CUL3 complex, ITC, cycloheximide chase, Co-IP with domain mutants

    PMID:23573258 PMID:23962426

    Open questions at the time
    • Kelch–WNK interface structure was not yet determined
    • Whether KLHL3 dimerization contributed to dominant inheritance was not addressed
  4. 2014 High

    The molecular basis for WNK degron recognition by KLHL3 was unresolved; the crystal structure of the Kelch domain bound to the WNK4 acidic degron peptide revealed the precise interface contacts disrupted by PHAII mutations on both proteins, and showed KLHL2 binds WNK kinases similarly.

    Evidence X-ray crystallography of KLHL3 Kelch–WNK4 degron complex, binding assays, mutagenesis

    PMID:24641320

    Open questions at the time
    • Recognition of other WNK isoforms and potential additional degron motifs was not characterized
    • Regulatory post-translational modifications of KLHL3 were unknown
  5. 2014 High

    Whether KLHL3 loss-of-function in vivo recapitulates PHAII through both WNK1 and WNK4 accumulation was untested; KLHL3 R528H knock-in mice exhibited PHAII with elevated WNK1 and WNK4, and biophysical measurements confirmed that neither kinase binds mutant KLHL3.

    Evidence KLHL3 R528H knock-in mice, fluorescence correlation spectroscopy with TAMRA-labeled peptides, immunoblot

    PMID:24821705

    Open questions at the time
    • Whether haploinsufficiency suffices for disease was not determined
    • Tissue distribution and non-renal roles of KLHL3 were unexplored
  6. 2015 High

    Whether CRL3-KLHL3 has substrates beyond WNK kinases was unknown; identification of claudin-8 as a direct KLHL3 substrate linked the ligase to paracellular chloride transport in the collecting duct, broadening its role beyond NCC regulation.

    Evidence Tissue-specific knockout mice, Co-IP, ubiquitination assay, paracellular permeability measurements

    PMID:25831548

    Open questions at the time
    • Whether claudin-8 dysregulation contributes to PHAII hypertension in patients was not established
    • Full substrate repertoire of CRL3-KLHL3 remained undefined
  7. 2015 High

    Upstream signals regulating KLHL3 activity were unknown; identification of Ser433 phosphorylation by Akt and PKA as a switch that disrupts WNK binding provided a mechanism by which insulin and vasopressin activate the WNK-NCC pathway.

    Evidence In vitro kinase assay, phospho-specific antibody, mass spectrometry, Co-IP after forskolin and insulin stimulation

    PMID:26435498

    Open questions at the time
    • In vivo relevance of S433 phosphorylation in intact kidney was not demonstrated
    • Additional regulatory kinases and phosphatases were not fully mapped
  8. 2015 Medium

    Whether KLHL3-mediated WNK degradation proceeds exclusively through the proteasome was untested; demonstration that p62-mediated selective autophagy also contributes to WNK4 clearance via KLHL3 expanded the degradative repertoire of this pathway.

    Evidence Proteasome and autophagy inhibitors, Co-IP of KLHL3–WNK4–p62 complex, colocalization with LC3

    PMID:26349538

    Open questions at the time
    • Relative contribution of autophagy vs proteasome to WNK degradation in vivo is unknown
    • Whether p62 is recruited directly by KLHL3 or by ubiquitinated WNK was not resolved
  9. 2017 High

    The mechanism of autosomal dominant inheritance in KLHL3 PHAII was unexplained by haploinsufficiency; KLHL3 knockout mice showed that heterozygous loss is insufficient for disease, and KLHL3 homodimerization provides the dominant-negative mechanism whereby one mutant subunit poisons the dimer.

    Evidence KLHL3 knockout mice with LacZ reporter, dimerization assays, comparison of heterozygous vs homozygous phenotypes

    PMID:28052936

    Open questions at the time
    • Stoichiometry of mutant/WT dimers and their residual activity were not quantified
    • Whether dominant-negative effects vary across KLHL3 mutations was not tested
  10. 2017 High

    Whether WNK1 or WNK4 is the primary mediator of NCC activation downstream of KLHL3 loss was debated; genetic epistasis in KLHL3 R528H × WNK4 knockout double-mutant mice demonstrated WNK4 is indispensable and WNK1 cannot compensate for its loss in activating SPAK–NCC.

    Evidence WNK4-/- × KLHL3 R528H/R528H double-mutant mice, immunoblot, immunofluorescence

    PMID:28743496

    Open questions at the time
    • Role of kidney-specific WNK1 isoform was not yet dissected
    • Contribution of WNK3 in vivo was not assessed
  11. 2018 High

    How CUL3 neddylation dynamics regulate KLHL3 stability in vivo was unclear; nephron-specific deletion of the COP9 signalosome subunit Jab1 showed that loss of deneddylase activity depletes KLHL3 and phenocopies WNK pathway activation, establishing CSN-mediated CUL3 deneddylation as essential for KLHL3 maintenance.

    Evidence Nephron-specific Jab1 (CSN5) knockout mice, western blot, immunofluorescence for KLHL3, WNK1/4, pNCC

    PMID:30301860

    Open questions at the time
    • Whether KLHL3 is degraded by auto-ubiquitination upon excessive CUL3 neddylation was not formally shown
    • Site of KLHL3 ubiquitination by neddylated CUL3 was not mapped
  12. 2021 High

    Whether KLHL3 discriminates among WNK1 isoforms was unknown; the kidney-specific WNK1 (KS-WNK1) was shown to be a preferential CRL3-KLHL3 substrate, with its unique N-terminal 30-amino acid sequence required for both NCC activation and KLHL3 recognition.

    Evidence KLHL3 R528H knock-in mice, mutagenesis of KS-WNK1 N-terminus, cell-based functional assays

    PMID:33682442

    Open questions at the time
    • Whether KS-WNK1 contains a distinct degron or uses the conserved acidic motif enhanced by its N-terminus was not structurally resolved
  13. 2022 High

    The complete WNK-family degron motif recognized by the KLHL3 Kelch domain had not been fully defined; crystal structure of KLHL3 with WNK3 peptide revealed an 11-residue motif and identified Thr541 as a WNK3-specific phosphorylatable residue whose modification abolishes KLHL3 binding, adding substrate-side phosphoregulation.

    Evidence X-ray crystallography, fluorescence polarization binding assays

    PMID:35179207

    Open questions at the time
    • Whether WNK3 Thr541 phosphorylation occurs in vivo and by which kinase was not determined
  14. 2022 Medium

    Whether KLHL3 has non-renal substrates was largely unexplored; identification of hnRNP Q1 as a KLHL3 substrate recruited by KSHV vIRF1 revealed a hijacking mechanism promoting aerobic glycolysis during viral infection.

    Evidence Co-IP, ubiquitination assay, siRNA knockdown, metabolic assays in KSHV-infected cells

    PMID:35538151

    Open questions at the time
    • Whether KLHL3 targets hnRNP Q1 independently of vIRF1 in uninfected cells is unknown
    • In vivo relevance during KSHV infection was not demonstrated
  15. 2023 Medium

    Whether WNK4 contains additional KLHL3-binding determinants beyond the canonical acidic degron was untested; a second C-terminal motif (CM, residues 1051-1075) was identified that independently mediates KLHL3-dependent degradation, though the canonical acidic motif is dominant.

    Evidence Deletion/mutagenesis constructs, Co-IP, western blot in transfected cells

    PMID:37285722

    Open questions at the time
    • Structural basis of CM recognition by KLHL3 is unknown
    • Whether CM contributes to WNK4 degradation in vivo was not tested
  16. 2025 Medium

    Whether O-GlcNAcylation regulates the KLHL3–WNK pathway was unknown; glycoproteomic analysis demonstrated that KLHL3 and all four WNK kinases are O-GlcNAcylated, with functional consequences for WNK4 activity in osmolarity sensing and ferroptosis.

    Evidence Biochemical O-GlcNAc enrichment, glycoproteomics/mass spectrometry, cell-based functional assays

    PMID:40796245

    Open questions at the time
    • Specific O-GlcNAcylation sites on KLHL3 and their effect on substrate binding or CUL3 interaction are not mapped
    • In vivo renal significance of KLHL3 O-GlcNAcylation is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full substrate repertoire of CRL3-KLHL3 beyond WNK kinases and claudin-8, the structural basis for KS-WNK1 preferential recognition, the in vivo significance of KLHL3 S433 phosphorylation and O-GlcNAcylation in the kidney, and whether KLHL3 plays physiological roles outside the nephron remain unresolved.
  • Complete substrate catalog of CRL3-KLHL3 is undefined
  • In vivo validation of KLHL3 regulatory phosphorylation (S433) in kidney is lacking
  • Non-renal physiological functions of KLHL3 are unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0060090 molecular adaptor activity 3
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 2 R-HSA-382551 Transport of small molecules 2
Partners
CLDN8COPS5CUL3SQSTM1WNK1WNK3WNK4
Complex memberships
CRL3-KLHL3 (CUL3-KLHL3 E3 ubiquitin ligase)

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 KLHL3 is a BTB-BACK-kelch family protein that acts as a substrate adaptor for Cullin3-based ubiquitin ligase complexes and downregulates NCC expression at the cell surface in the distal nephron; loss-of-function mutations in KLHL3 cause familial hyperkalemic hypertension by impairing ion transport. Linkage analysis, whole-exome sequencing, direct sequencing, cell surface expression assays Nature genetics High 22406640
2013 KLHL3 associates with WNK isoforms (WNK1, WNK4) and CUL3 to form a CUL3-KLHL3 E3 ubiquitin ligase complex that ubiquitylates WNK1 in vitro; disease-causing KLHL3 mutations inhibit binding to WNK1 or CUL3, and disease-causing WNK4 mutations (E562K, Q565E) abolish interaction with KLHL3; siRNA knockdown of CUL3 increases WNK1 protein levels and kinase activity. Co-immunoprecipitation, in vitro ubiquitylation assay, siRNA knockdown, domain mapping The Biochemical journal High 23387299
2013 KLHL3 interacts with CUL3 and WNK4, induces WNK4 ubiquitination, and reduces WNK4 protein levels; PHAII-causing mutations in either KLHL3 or WNK4 reduce their interaction, decrease WNK4 ubiquitination, and increase WNK4 protein levels leading to hypertension. Co-immunoprecipitation, ubiquitination assay, transgenic mice overexpressing WNK4, WNK4 D561A knock-in mouse model Cell reports High 23453970
2013 Crystal structure of the KLHL3 BTB-BACK domain dimer in complex with an N-terminal fragment of CUL3 reveals that both BTB and BACK domains contribute to the CUL3 interaction surface; ITC demonstrates that disease mutations in KLHL3 BTB-BACK domains disrupt CUL3 association. X-ray crystallography, isothermal titration calorimetry (ITC), mutagenesis PloS one High 23573258
2013 Disease-causing KLHL3 mutations in distinct domains impair WNK4 ubiquitination through different mechanisms: BTB domain mutation (E85A) and BACK domain mutation (C164F) decrease CUL3 binding; Kelch domain mutations (S410L, R528H) decrease WNK4 binding; S410L mutation also reduces KLHL3 intracellular stability. Co-immunoprecipitation, cycloheximide chase assay, in vitro/in vivo ubiquitination assays, transient transfection in HEK293T cells Biochemical and biophysical research communications High 23962426
2013 KLHL3 decreases WNK4 protein abundance and inhibits WNK4-mediated NCC activation in Xenopus oocytes; KLHL3-induced WNK4 ubiquitination and degradation is blocked by dominant-negative Cullin3; five PHAII-causing KLHL3 mutations disrupt WNK4 regulation. Xenopus oocyte expression system, ubiquitination assay, dominant-negative Cullin3 construct FEBS letters High 23665031
2014 Crystal structure of the KLHL3 Kelch domain in complex with the WNK4 degron motif reveals an intricate web of interactions between conserved residues on the Kelch β-propeller surface and the WNK4 acidic degron; disease-causing mutations in both proteins disrupt critical interface contacts; KLHL2 binds WNK kinases in a similar manner. X-ray crystallography, binding assays, mutagenesis The Biochemical journal High 24641320
2014 FHHt-causing CUL3 Δ403-459 mutant is more heavily neddylated and activated than WT CUL3, retains ability to bind and ubiquitylate KLHL3, and causes excess degradation of KLHL3, thereby preventing WNK kinase degradation despite increased CUL3-mediated WNK ubiquitylation; nephron-specific Cul3 deletion in mice increases WNK kinase levels and phosphorylated NCC. Cell-based ubiquitylation assays, neddylation analysis, nephron-specific Cul3 knockout mouse, western blot The Journal of clinical investigation High 25250572
2014 KLHL3 R528H knock-in mice exhibit PHAII phenotypes with increased WNK1 and WNK4 protein levels in kidney; fluorescence correlation spectroscopy confirmed that neither WNK1 nor WNK4 can bind mutant KLHL3 R528H, establishing that impaired KLHL3-CUL3-mediated ubiquitination of both WNK1 and WNK4 causes PHAII. KLHL3 R528H knock-in mice, immunoblot, fluorescence correlation spectroscopy with TAMRA-labeled peptides Human molecular genetics High 24821705
2015 KLHL3 directly binds claudin-8 and mediates its ubiquitination and degradation; dominant PHAII KLHL3 mutation impairs claudin-8 binding, ubiquitination, and degradation; loss of claudin-8 disrupts paracellular chloride transport in the collecting duct by delocalization of claudin-4 from the tight junction. Tissue-specific knockout mouse, Co-immunoprecipitation, ubiquitination assay, KLHL3 knockdown, paracellular permeability assay Proceedings of the National Academy of Sciences of the United States of America High 25831548
2015 Akt and PKA phosphorylate KLHL3 at serine 433 in vitro; phosphorylated KLHL3 (S433) shows defective binding to WNK4; PKA stimulation (forskolin) increases S433 phosphorylation and WNK4 protein levels in HEK293 cells; insulin also increases KLHL3 S433 phosphorylation, providing a mechanism for insulin/vasopressin-mediated WNK pathway activation. Mass spectrometry, phospho-specific antibody, in vitro kinase assay, Co-immunoprecipitation, cell-based assays with PKA stimulator Biochemical and biophysical research communications High 26435498
2015 KLHL3-induced WNK4 degradation involves not only proteasomal but also p62-mediated selective autophagy; KLHL3 forms a complex with both WNK4 and p62 via its kelch repeat domain; WNK4 colocalizes with KLHL3, p62, and LC3 (autophagosome marker) in cytoplasmic puncta. Co-immunoprecipitation, proteasome/autophagy inhibitors, p62 overexpression/knockdown, immunofluorescence The Biochemical journal Medium 26349538
2017 KLHL3-/- mice show PHAII-like phenotypes with increased WNK1 and WNK4 only in the kidney; KLHL3+/- mice do not exhibit PHAII, demonstrating that KLHL3 haploinsufficiency is insufficient to cause disease; dominant-negative effect of mutant KLHL3 in autosomal dominant PHAII is explained by KLHL3 dimerization. KLHL3 knockout mice (LacZ reporter), immunoblot, β-galactosidase staining, dimerization assays Molecular and cellular biology High 28052936
2017 WNK4 is indispensable for OSR1/SPAK-NCC phosphorylation cascade; in KLHL3 R528H/R528H mice (extremely elevated WNK1), absence of WNK4 almost completely abolishes SPAK and NCC phosphorylation, demonstrating WNK1 cannot compensate for WNK4 in activating NCC. WNK4-/- × KLHL3 R528H knock-in double-mutant mice, immunoblot, immunofluorescence Biochemical and biophysical research communications High 28743496
2018 KLHL3 BTB domain mutation (M131V/M78V human equivalent) retains intact WNK binding but reduces CUL3 binding, leading to increased WNK1 and WNK4 abundance and NCC phosphorylation; knock-in mice exhibit PHAII phenotype with decreased cytosolic CUL3 in distal convoluted tubule cells. KLHL3 M131V knock-in mice, co-immunoprecipitation, immunoblot, immunogold-labeling electron microscopy, microdissected renal tubules FASEB journal High 30148674
2018 Decreased KLHL3 is specifically caused by FHHt-associated mutant CUL3 (Δexon9); CUL3Δex9 knock-in mice show markedly decreased KLHL3 but comparable levels of KLHL2 and other KLHL proteins, confirming that KLHL3 degradation is specific to mutant CUL3. CUL3 Δex9 knock-in mice, immunoblot with validated KLHL3 antibody Clinical and experimental nephrology Medium 29869755
2018 Renal deletion of CSN subunit Jab1 (deneddylase) increases neddylated CUL3, almost completely depletes KLHL3, and substantially elevates WNK1, WNK4, and SPAK, with increased phosphorylated NCC; demonstrates that COP9 signalosome activity is required to maintain KLHL3 stability and normal WNK signaling. Nephron-specific Jab1 (CSN5) knockout mice, western blot, immunofluorescence Journal of the American Society of Nephrology High 30301860
2021 The kidney-specific WNK1 isoform (KS-WNK1) is preferentially targeted for degradation by the CUL3-KLHL3 E3 ligase compared to full-length WNK1; the unique 30-amino acid N-terminal fragment of KS-WNK1 is essential for both its activation of NCC and recognition by KLHL3; KLHL3 R528H knock-in mice show specifically increased KS-WNK1. KLHL3 R528H knock-in mice, mutagenesis of KS-WNK1, cell-based functional assays, immunoblot American journal of physiology. Renal physiology High 33682442
2022 KLHL3 is recruited by viral IRF1 (vIRF1) of KSHV to ubiquitinate and degrade hnRNP Q1 through the ubiquitin-proteasome pathway, thereby destabilizing GDPD1 mRNA and enhancing aerobic glycolysis. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, metabolic assays Cell death and differentiation Medium 35538151
2022 Crystal structure of the KLHL3 Kelch domain with WNK3 peptide reveals the complete 11-mer WNK-family degron motif including conserved salt bridge and hydrogen bond interactions; WNK3 Thr541 substitutes the second proline, providing a unique phosphorylatable residue whose phosphorylation abrogates KLHL3 interaction. X-ray crystallography, fluorescence polarization, structural modeling The Biochemical journal High 35179207
2022 KLHL3 interacts with cMyBP-C by co-immunoprecipitation and mediates its ubiquitination and degradation; homocysteine treatment increases KLHL3 expression and decreases cMyBP-C, which is reversed by proteasome inhibitor MG132. Co-immunoprecipitation, immunofluorescence, ubiquitination assay, western blot Experimental cell research Low 28315668
2023 A novel C-terminal motif (CM, residues 1051-1075) in WNK4, rich in negatively charged residues, mediates KLHL3-dependent degradation independently of the acidic motif (AM); both AM and CM respond similarly to KLHL3 Kelch domain PHAII mutations, but AM is dominant. Co-immunoprecipitation, deletion/mutagenesis constructs, western blot in transfected cells Biochemical and biophysical research communications Medium 37285722
2025 Human KLHL3 and all four WNK kinases (WNK1-4) are O-GlcNAcylated; O-GlcNAcylation functionally regulates the KLHL3/WNK pathway and affects WNK4 function in osmolarity control and ferroptosis. Biochemical O-GlcNAc enrichment, glycoproteomics/mass spectrometry, cell-based functional assays Glycobiology Medium 40796245

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nature genetics 263 22406640
2013 The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. The Biochemical journal 180 23387299
2013 Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension. Cell reports 180 23453970
2014 Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3. The Journal of clinical investigation 123 25250572
2014 Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice. Human molecular genetics 71 24821705
2013 Crystal structure of KLHL3 in complex with Cullin3. PloS one 66 23573258
2014 Structural and biochemical characterization of the KLHL3-WNK kinase interaction important in blood pressure regulation. The Biochemical journal 61 24641320
2013 Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation. FEBS letters 58 23665031
2015 KLHL3 regulates paracellular chloride transport in the kidney by ubiquitination of claudin-8. Proceedings of the National Academy of Sciences of the United States of America 53 25831548
2017 KLHL3 Knockout Mice Reveal the Physiological Role of KLHL3 and the Pathophysiology of Pseudohypoaldosteronism Type II Caused by Mutant KLHL3. Molecular and cellular biology 48 28052936
2014 Detection of mutations in KLHL3 and CUL3 in families with FHHt (familial hyperkalaemic hypertension or Gordon's syndrome). Clinical science (London, England : 1979) 41 24266877
2013 Decrease of WNK4 ubiquitination by disease-causing mutations of KLHL3 through different molecular mechanisms. Biochemical and biophysical research communications 34 23962426
2015 Impaired degradation of WNK by Akt and PKA phosphorylation of KLHL3. Biochemical and biophysical research communications 29 26435498
2018 Renal COP9 Signalosome Deficiency Alters CUL3-KLHL3-WNK Signaling Pathway. Journal of the American Society of Nephrology : JASN 24 30301860
2021 Role of KLHL3 and dietary K+ in regulating KS-WNK1 expression. American journal of physiology. Renal physiology 23 33682442
2017 WNK4 is indispensable for the pathogenesis of pseudohypoaldosteronism type II caused by mutant KLHL3. Biochemical and biophysical research communications 23 28743496
2018 Decreased KLHL3 expression is involved in the pathogenesis of pseudohypoaldosteronism type II caused by cullin 3 mutation in vivo. Clinical and experimental nephrology 19 29869755
2000 Molecular characterization of KLHL3, a human homologue of the Drosophila kelch gene. Genomics 19 10843806
2022 A viral interferon regulatory factor degrades RNA-binding protein hnRNP Q1 to enhance aerobic glycolysis via recruiting E3 ubiquitin ligase KLHL3 and decaying GDPD1 mRNA. Cell death and differentiation 18 35538151
2016 Phosphorylation of KLHL3 at serine 433 impairs its interaction with the acidic motif of WNK4: a molecular dynamics study. Protein science : a publication of the Protein Society 16 27727489
2021 Decreased KLHL3 expression is involved in the activation of WNK-OSR1/SPAK-NCC cascade in type 1 diabetic mice. Pflugers Archiv : European journal of physiology 15 33432425
2016 The CUL3/KLHL3-WNK-SPAK/OSR1 pathway as a target for antihypertensive therapy. American journal of physiology. Renal physiology 15 27076645
2017 Three cases of Gordon syndrome with dominant KLHL3 mutations. Journal of pediatric endocrinology & metabolism : JPEM 12 28222034
2015 Involvement of selective autophagy mediated by p62/SQSTM1 in KLHL3-dependent WNK4 degradation. The Biochemical journal 10 26349538
2018 Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 9 30148674
2016 A patient with pseudohypoaldosteronism type II complicated by congenital hypopituitarism carrying a KLHL3 mutation. Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 9 27780982
2015 Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations. Nephron 9 25925082
2022 A Novel Homozygous KLHL3 Mutation as a Cause of Autosomal Recessive Pseudohypoaldosteronism Type II Diagnosed Late in Life. Nephron 8 35093948
2017 cMyBP-C was decreased via KLHL3-mediated proteasomal degradation in congenital heart diseases. Experimental cell research 8 28315668
2017 Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter. Nephron 8 28511177
2019 Unveiling the Distinct Mechanisms by which Disease-Causing Mutations in the Kelch Domain of KLHL3 Disrupt the Interaction with the Acidic Motif of WNK4 through Molecular Dynamics Simulation. Biochemistry 7 30931564
2022 KLHL3 deficiency in mice ameliorates obesity, insulin resistance, and nonalcoholic fatty liver disease by regulating energy expenditure. Experimental & molecular medicine 5 36028759
2021 A case report of pseudohypoaldosteronism type II with a homozygous KLHL3 variant accompanied by hyperthyroidism. BMC endocrine disorders 5 34022862
2022 Sequence and structural variations determining the recruitment of WNK kinases to the KLHL3 E3 ligase. The Biochemical journal 4 35179207
2023 KLHL3-dependent WNK4 degradation affected by potassium through the neddylation and autophagy pathway. BMC nephrology 3 37481568
2025 The functional study of novel KLHL3 missense mutations associated with pseudohypoaldosteronism type II. Endocrine 1 41091294
2024 Pseudohypoaldosteronism type II and sensory neuropathy associated with a heterozygous pathogenic variant in KLHL3 gene, a case report. Heliyon 1 39553548
2023 Identification of a novel KLHL3-interacting motif in the C-terminal region of WNK4. Biochemical and biophysical research communications 1 37285722
2022 Generation and analysis of pseudohypoaldosteronism type II knock-in mice caused by a nonsense KLHL3 mutation in the Kelch domain. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1 35621709
2019 KLHL3 single-nucleotide polymorphism is associated with essential hypertension in Chinese Han population. Medicine 1 31096542
2025 Camk2n1 deficiency reduces the NaCl cotransporter activity through the CUL3/KLHL3/WNK4 complex in the kidney. European journal of pharmacology 0 39798916
2025 Evidence for Functional Regulation of the KLHL3/WNK Pathway by O-GlcNAcylation. bioRxiv : the preprint server for biology 0 40060460
2025 Evidence for functional regulation of the KLHL3/WNK pathway by O-GlcNAcylation. Glycobiology 0 40796245
2025 Pseudo-Hypoaldosteronism Type 2 due to New Variants of KLHL3 Gene Diagnosed in an Adult Woman With Very High Sensitivity to Hydrochlorothiazide. Clinical case reports 0 40964474
2021 [A Case of Pseudohypoaldosteronism Type Ⅱ (PHA2) Caused by a Novel Mutation of KLHL3]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 0 34622611