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J. Biol. Chem., Vol. 281, Issue 24, 16323-16332, June 16, 2006

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14-3-3 Isoforms Are Induced by Aldosterone and Participate in Its Regulation of Epithelial Sodium Channels^*

From the Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Aldosterone increases sodium absorption across renal collecting duct cells primarily by increasing the apical membrane expression of ENaC, the sodium entry channel. Nedd4-2, a ubiquitin-protein isopeptide ligase, tags ENaC with ubiquitin for internalization and degradation, but when it is phosphorylated by the aldosterone-induced kinase, SGK1, Nedd4-2 is inhibited and apical ENaC density and sodium absorption increase. We evaluated the hypothesis that 14-3-3 proteins participate in the aldosterone-mediated regulation of ENaC by associating with phosphorylated Nedd4-2. Mouse cortical collecting duct (mCCD) epithelia cultured on filters expressed several 14-3-3 isoforms; this study focused on an isoform whose expression was induced 3-fold by aldosterone, 14-3-3. In polarized mCCD epithelia, aldosterone elicited significant, time-dependent increases in the expression of -ENaC, SGK1, phospho-Nedd4-2, and 14-3-3 without altering total Nedd4-2. Aldosterone decreased the interaction of -ENaC with Nedd4-2, and with similar kinetics increased the association of 14-3-3 with phospho-Nedd4-2. Short interfering RNA-induced knockdown of 14-3-3 blunted the aldosterone-induced increase in -ENaC expression, returned -ENaC-Nedd4-2 binding toward prealdosterone levels, and blocked the aldosterone-stimulated increase in transepithelial sodium transport. Incubation of cell extracts with a selective phospho-Nedd4-2 antibody blocked the aldosterone-induced association of 14-3-3 with Nedd4-2, implicating SGK1 phosphorylation at Ser-328 as the primary site of 14-3-3 binding. Our studies show that aldosterone increases the expression of 14-3-3, which interacts with phospho-Nedd4-2 to block its interaction with ENaC, thus enhancing sodium absorption by increasing apical membrane ENaC density.

Received for publication, February 13, 2006 , and in revised form, March 30, 2006.

^* This work was supported by National Institutes of Health Grants DK54814 and DK72506 and by grants from the Cystic Fibrosis Foundation. 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: Dept. of Cell Biology and Physiology, University of Pittsburgh School of Medicine, 3500 Terrace St., Pittsburgh, PA 15261. Tel.: 412-648-9498; Fax: 412-648-8330; E-mail: frizzell{at}pitt.edu.

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