KLHL2 interacts with and ubiquitinates WNK kinases.
Mutations in the WNK1 and WNK4 genes result in an inherited hypertensive disease, pseudohypoaldosteronism type II (PHAII). Recently, the KLHL3 and Cullin3 genes were also identified as responsible genes for PHAII. Although we have reported that WNK4 is a substrate for the KLHL3-Cullin3 E3 ligase complex, it is not clear whether all of the WNK isoforms are regulated only by KLHL3. To explore the interaction of WNKs and other Kelch-like proteins, we focused on KLHL2 (Mayven), a human homolog of Drosophila Kelch that shares the highest similarity with KLHL3. We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body.
['Takahashi|Daiei|D|', 'Mori|Takayasu|T|', 'Wakabayashi|Mai|M|', 'Mori|Yutaro|Y|', 'Susa|Koichiro|K|', 'Zeniya|Moko|M|', 'Sohara|Eisei|E|', 'Rai|Tatemitsu|T|', 'Sasaki|Sei|S|', 'Uchida|Shinichi|S|']
D048868:Adaptor Proteins, Signal Transducing D000595:Amino Acid Sequence D002352:Carrier Proteins D057809:HEK293 Cells D006801:Humans D006863:Hydrogen-Ion Concentration D047908:Intracellular Signaling Peptides and Proteins D008840:Microfilament Proteins D015778:Minor Histocompatibility Antigens D008969:Molecular Sequence Data D009419:Nerve Tissue Proteins D011485:Protein Binding D017346:Protein Serine-Threonine Kinases D017434:Protein Structure, Tertiary D044767:Ubiquitin-Protein Ligases D000076204:WNK Lysine-Deficient Protein Kinase 1
Ubiquitination WNK kinase Cullin-3 Kelch-like protein 2