Figure 1. Regulation of WNK signaling by KLHL3–CUL3 complex.

Under normal conditions, protein levels of WNK1 and WNK4 in DCT are maintained by degradation through ubiquitination by the KLHL3–CUL3 E3 ligase complex. NEDD is responsible for ENaC disposal, also by ubiquitination (left). WNK1 and WNK4 regulate OSR1 and SPAK, which in turn regulate NCC, all for the purpose of sodium and chloride reabsorption.