WNK4 enhances the degradation of NCC through a sortilin-mediated lysosomal pathway.
WNK kinase is a serine/threonine kinase that plays an important role in electrolyte homeostasis. WNK4 significantly inhibits the surface expression of the sodium chloride co-transporter (NCC) by enhancing the degradation of NCC through a lysosomal pathway, but the mechanisms underlying this trafficking are unknown. Here, we investigated the effect of the lysosomal targeting receptor sortilin on NCC expression and degradation. In Cos-7 cells, we observed that the presence of WNK4 reduced the steady-state amount of NCC by approximately half. Co-transfection with truncated sortilin (a dominant negative mutant) prevented this WNK4-induced reduction in NCC. NCC immunoprecipitated with both wild-type sortilin and, to a lesser extent, truncated sortilin. Immunostaining revealed that WNK4 increased the co-localization of NCC with the lysosomal marker cathepsin D, and NCC co-localized with wild-type sortilin, truncated sortilin, and WNK4 in the perinuclear region. These findings suggest that WNK4 promotes NCC targeting to the lysosome for degradation via a mechanism involving sortilin.
Zhou
Bo
B
Second Affiliated Hospital, Wenzhou Medical College, Zhejiang, China.
Zhuang
Jieqiu
J
Gu
Dingying
D
Wang
Hua
H
Cebotaru
Liudmila
L
Guggino
William B
WB
Cai
Hui
H
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002402:Cathepsin D / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D007686:Kidney Tubules, Distal / Q000166:cytology / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D049992:Sodium Chloride Symporters / Q000378:metabolism*; D014162:Transfection; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D002402:Cathepsin D; D017346:Protein Serine-Threonine Kinases; D049992:Sodium Chloride Symporters; D000099183:Sortilin; C433806:WNK4 protein, human