NDLI: Functional Regulation of the Epithelial Na+ Channel by IκB Kinase-β Occurs via Phosphorylation of the Ubiquitin Ligase Nedd4-2*

Content Provider	PubMed Central
Author	Edinger, Robert S. Lebowitz, Jonathan Li, Hui Alzamora, Rodrigo Wang, Huamin Johnson, John P. Hallows, Kenneth R.
Abstract	We have previously shown that IκB kinase-β (IKKβ) interacts with the epithelial Na+ channel (ENaC) β-subunit and enhances ENaC activity by increasing its surface expression in Xenopus oocytes. Here, we show that the IKKβ-ENaC interaction is physiologically relevant in mouse polarized kidney cortical collecting duct (mpkCCDc14) cells, as RNA interference-mediated knockdown of endogenous IKKβ in these cells by ∼50% resulted in a similar reduction in transepithelial ENaC-dependent equivalent short circuit current. Although IKKβ binds to ENaC, there was no detectable phosphorylation of ENaC subunits by IKKβ in vitro. Because IKKβ stimulation of ENaC activity occurs through enhanced channel surface expression and the ubiquitin-protein ligase Nedd4-2 has emerged as a central locus for ENaC regulation at the plasma membrane, we tested the role of Nedd4-2 in this regulation. IKKβ-dependent phosphorylation of Xenopus Nedd4-2 expressed in HEK-293 cells occurred both in vitro and in vivo, suggesting a potential mechanism for regulation of Nedd4-2 and thus ENaC activity. 32P labeling studies utilizing wild-type or mutant forms of Xenopus Nedd4-2 demonstrated that Ser-444, a key SGK1 and protein kinase A-phosphorylated residue, is also an important IKKβ phosphorylation target. ENaC stimulation by IKKβ was preserved in oocytes expressing wild-type Nedd4-2 but blocked in oocytes expressing either a dominant-negative (C938S) or phospho-deficient (S444A) Nedd4-2 mutant, suggesting that Nedd4-2 function and phosphorylation by IKKβ are required for IKKβ regulation of ENaC. In summary, these results suggest a novel mode of ENaC regulation that occurs through IKKβ-dependent Nedd4-2 phosphorylation at a recognized SGK1 and protein kinase A target site.
Related Links	http://dx.doi.org/10.1074/jbc.M807358200
Starting Page	150
File Format	PDF
ISSN	1083351X
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	1
Volume Number	284
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2009-01-02
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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