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1 Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, USA; Graduate Program in Molecular Biology, University of Iowa College of Medicine, Iowa City, IA, USA
2 Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, USA; Veterans Affairs Medical Center, Iowa City, IA, USA
3 Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, USA; Graduate Program in Molecular Biology, University of Iowa College of Medicine, Iowa City, IA, USA; Veterans Affairs Medical Center, Iowa City, IA, USA
* To whom correspondence should be addressed. E-mail: christie-thomas{at}uiowa.edu.
Mutations that disrupt a PY motif in epithelial Na+ channel (ENaC) subunits increase surface expression of Na+ channels in the collecting duct, resulting in greater Na+ reabsorption. Nedd4 and Nedd4-2 have been identified as ubiquitin ligases that can interact with ENaC via its PY motifs to regulate channel activity. We recently reported that human Nedd4-2 (hNedd4-2) is expressed as many isoforms due to alternative promoter usage and/or variable splicing. To understand the relevance of hNedd4-2 isoforms for collecting duct Na+ transport, we studied the interaction with ENaC, the intracellular localization and function of three naturally occurring hNedd4-2 isoforms: full length Nedd4-2 (Nedd4-2), Nedd4-2 lacking the N-terminal C2 domain (Nedd4-2
C2) and Nedd4-2 lacking the C2 domain and WW domains 2 and 3 (Nedd4-2WW2,3). Nedd4-2 and Nedd4-2C2 associate with ENaC and robustly reduce Na+ transport in Xenopus oocytes, while the interaction with and functional effect of Nedd4- 2WW2,3 on ENaC is weak. Nedd4-2 is expressed in the mouse collecting duct and overexpression of Nedd4-2 reduces endogenous ENaC activity in a collecting duct cell line. This reduction in ENaC activity can be reversed early with exposure to dexamethasone, an effect that is associated with an increase in sgk1 abundance. The C2 domain is required to target Nedd4-2 to the plasma membrane in response to elevation of intracellular calcium concentration ([Ca2+]i) in MDCK cells, though it does not appear to mediate the inhibitory effect of [Ca2+]i on Na+ transport. Our data illustrate that naturally occurring hNedd4-2 isoforms differentially associate with ENaC to regulate its activity.
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