WNK4 enhances the degradation of NCC through a sortilin-mediated lysosomal pathway

Bo Zhou, Jieqiu Zhuang, Dingying Gu, Hua Wang, Liudmila Cebotaru, William B. Guggino, Hui Cai

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67 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)82-92
Number of pages11
JournalJournal of the American Society of Nephrology
Issue number1
StatePublished - Jan 2010

ASJC Scopus subject areas

  • Nephrology


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