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J. Biol. Chem., Vol. 283, Issue 10, 6033-6039, March 7, 2008

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Nedd4-2 Induces Endocytosis and Degradation of Proteolytically Cleaved Epithelial Na⁺ Channels^*

From the Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, Iowa 52242

As a pathway for Na⁺ reabsorption, the epithelial Na⁺ channel ENaC is critical for Na⁺ homeostasis and blood pressure control. Na⁺ transport is regulated by Nedd4-2, an E3 ubiquitin ligase that decreases ENaC expression at the cell surface. To investigate the underlying mechanisms, we proteolytically cleaved/activated ENaC at the cell surface and then quantitated the rate of disappearance of cleaved channels using electrophysiological and biochemical assays. We found that cleaved ENaC channels were rapidly removed from the cell surface. Deletion or mutation of the Nedd4-2 binding motifs in , β, and ENaC dramatically reduced endocytosis, whereas a mutation that disrupts a YXXØ endocytosis motif had no effect. ENaC endocytosis was also decreased by silencing of Nedd4-2 and by expression of a dominant negative Nedd4-2 construct. Conversely, Nedd4-2 overexpression increased ENaC endocytosis in human embryonic kidney 293 cells but had no effect in Fischer rat thyroid epithelia. In addition to its effect on endocytosis, Nedd4-2 also increased the rate of degradation of the cell surface pool of cleaved ENaC. Together the data indicate that Nedd4-2 reduces ENaC surface expression by altering its trafficking at two distinct sites in the endocytic pathway, inducing endocytosis of cleaved channels and targeting them for degradation.

Received for publication, October 15, 2007 , and in revised form, January 2, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 371 EMRB, University of Iowa College of Medicine, Iowa City, IA 52242. E-mail: peter-snyder{at}uiowa.edu.

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