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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 and Hui Cai^*,

Renal Division, Second Affiliated Hospital, Wenzhou Medical College, Zhejiang, China;
^* Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Correspondence: Dr. Hui Cai, Renal Division, Emory University School of Medicine, 1639 Pierce Drive, WMB Room 338, Atlanta, GA 30322. Phone: 404-712-1096; Fax: 404-727-3425; E-mail: hcai3{at}emory.edu or Dr. Dingying Gu, Renal Division, The Second Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang 325000, China. Phone: 86-577-8881-6381; Fax: 86-577-8883-2693; E-mail: dingyinggu{at}hotmail.com

Received for publication December 18, 2008. Accepted for publication September 16, 2009.

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.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673