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J Biol Chem
2009 Jan 02;2841:150-157. doi: 10.1074/jbc.M807358200.
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Functional regulation of the epithelial Na+ channel by IkappaB kinase-beta occurs via phosphorylation of the ubiquitin ligase Nedd4-2.
Edinger RS
,
Lebowitz J
,
Li H
,
Alzamora R
,
Wang H
,
Johnson JP
,
Hallows KR
.
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We have previously shown that IkappaB kinase-beta (IKKbeta) interacts with the epithelial Na+ channel (ENaC) beta-subunit and enhances ENaC activity by increasing its surface expression in Xenopus oocytes. Here, we show that the IKKbeta-ENaC interaction is physiologically relevant in mouse polarized kidney cortical collecting duct (mpkCCDc14) cells, as RNA interference-mediated knockdown of endogenous IKKbeta in these cells by approximately 50% resulted in a similar reduction in transepithelial ENaC-dependent equivalent short circuit current. Although IKKbeta binds to ENaC, there was no detectable phosphorylation of ENaC subunits by IKKbeta in vitro. Because IKKbeta 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. IKKbeta-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 IKKbeta phosphorylation target. ENaC stimulation by IKKbeta 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 IKKbeta are required for IKKbeta regulation of ENaC. In summary, these results suggest a novel mode of ENaC regulation that occurs through IKKbeta-dependent Nedd4-2 phosphorylation at a recognized SGK1 and protein kinase A target site.
Abriel,
Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle's syndrome.
1999, Pubmed,
Xenbase
Abriel,
Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle's syndrome.
1999,
Pubmed
,
Xenbase
Bhalla,
Serum- and glucocorticoid-regulated kinase 1 regulates ubiquitin ligase neural precursor cell-expressed, developmentally down-regulated protein 4-2 by inducing interaction with 14-3-3.
2005,
Pubmed
Bhalla,
AMP-activated kinase inhibits the epithelial Na+ channel through functional regulation of the ubiquitin ligase Nedd4-2.
2006,
Pubmed
,
Xenbase
Bhalla,
Mechanisms of ENaC regulation and clinical implications.
2008,
Pubmed
Booth,
Targeted degradation of ENaC in response to PKC activation of the ERK1/2 cascade.
2003,
Pubmed
Carattino,
Epithelial sodium channel inhibition by AMP-activated protein kinase in oocytes and polarized renal epithelial cells.
2005,
Pubmed
,
Xenbase
Dagenais,
Downregulation of ENaC activity and expression by TNF-alpha in alveolar epithelial cells.
2004,
Pubmed
Debonneville,
Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression.
2001,
Pubmed
,
Xenbase
DiPetrillo,
Tumor necrosis factor induces sodium retention in diabetic rats through sequential effects on distal tubule cells.
2004,
Pubmed
Dieter,
Regulation of glucose transporter SGLT1 by ubiquitin ligase Nedd4-2 and kinases SGK1, SGK3, and PKB.
2004,
Pubmed
,
Xenbase
Dinudom,
The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels.
2004,
Pubmed
Fotia,
Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2.
2004,
Pubmed
,
Xenbase
Fukuda,
Mechanisms of TNF-alpha stimulation of amiloride-sensitive sodium transport across alveolar epithelium.
2001,
Pubmed
Giri,
5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase.
2004,
Pubmed
Henke,
Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1.
2004,
Pubmed
,
Xenbase
Huang,
Metformin inhibits TNF-alpha-induced IkappaB kinase phosphorylation, IkappaB-alpha degradation and IL-6 production in endothelial cells through PI3K-dependent AMPK phosphorylation.
2009,
Pubmed
Häcker,
Regulation and function of IKK and IKK-related kinases.
2006,
Pubmed
Ichimura,
14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase.
2005,
Pubmed
,
Xenbase
Jespersen,
The KCNQ1 potassium channel is down-regulated by ubiquitylating enzymes of the Nedd4/Nedd4-like family.
2007,
Pubmed
Lang,
betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932.
2003,
Pubmed
Lebowitz,
Ikappab kinase-beta (ikkbeta) modulation of epithelial sodium channel activity.
2004,
Pubmed
,
Xenbase
Liang,
14-3-3 isoforms are induced by aldosterone and participate in its regulation of epithelial sodium channels.
2006,
Pubmed
Mall,
Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice.
2004,
Pubmed
Mohan,
Differential current decay profiles of epithelial sodium channel subunit combinations in polarized renal epithelial cells.
2004,
Pubmed
Palmada,
Regulation of intestinal phosphate cotransporter NaPi IIb by ubiquitin ligase Nedd4-2 and by serum- and glucocorticoid-dependent kinase 1.
2004,
Pubmed
,
Xenbase
Palmada,
Serum and glucocorticoid inducible kinases functionally regulate ClC-2 channels.
2004,
Pubmed
,
Xenbase
Rezaiguia,
Acute bacterial pneumonia in rats increases alveolar epithelial fluid clearance by a tumor necrosis factor-alpha-dependent mechanism.
1997,
Pubmed
Rodríguez-Iturbe,
Interstitial inflammation, sodium retention, and the pathogenesis of nephrotic edema: a unifying hypothesis.
2002,
Pubmed
Sakurai,
IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain.
1999,
Pubmed
,
Xenbase
Sanchez-Perez,
GRK2 interacts with and phosphorylates Nedd4 and Nedd4-2.
2007,
Pubmed
Shi,
Interactions of beta and gamma ENaC with Nedd4 can be facilitated by an ERK-mediated phosphorylation.
2002,
Pubmed
,
Xenbase
Snyder,
cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2.
2004,
Pubmed
Snyder,
Minireview: regulation of epithelial Na+ channel trafficking.
2005,
Pubmed
Vinciguerra,
Cytokines and sodium induce protein kinase A-dependent cell-surface Na,K-ATPase recruitment via dissociation of NF-kappaB/IkappaB/protein kinase A catalytic subunit complex in collecting duct principal cells.
2005,
Pubmed
Wu,
Differential phosphorylation of the signal-responsive domain of I kappa B alpha and I kappa B beta by I kappa B kinases.
2003,
Pubmed
Wu,
Adiponectin suppresses IkappaB kinase activation induced by tumor necrosis factor-alpha or high glucose in endothelial cells: role of cAMP and AMP kinase signaling.
2007,
Pubmed
Zandi,
The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation.
1997,
Pubmed
de Seigneux,
NF-kappaB inhibits sodium transport via down-regulation of SGK1 in renal collecting duct principal cells.
2008,
Pubmed