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Mol Cell Biol
2004 Mar 01;246:2397-409. doi: 10.1128/MCB.24.6.2397-2409.2004.
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Participation of the ubiquitin-conjugating enzyme UBE2E3 in Nedd4-2-dependent regulation of the epithelial Na+ channel.
Debonneville C
,
Staub O
.
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The epithelial Na+ channel (ENaC) is a heteromeric protein complex playing a fundamental role in Na+ homeostasis and blood pressure regulation. Specific mutations inactivating PY motifs in ENaC C termini cause Liddle's syndrome, an inherited form of hypertension. Previously we showed that these PY motifs serve as binding sites for the E3 enzyme Nedd4-2, implying ubiquitination as a regulatory mechanism of ENaC. Ubiquitination involves the sequential action of E1, E2, and E3 enzymes. Here we identify the E2 enzyme UBE2E3, which acts in concert with Nedd4-2, and show by coimmunoprecipitation that UBE2E3 and Nedd4-2 interact together. In Xenopus laevis oocytes, UBE2E3 reduces ENaC activity marginally, consistent with Nedd4-2 being the rate-limiting factor in this process, whereas a catalytically inactive mutant of UBE2E3 (UBE2E3-CS) causes elevated ENaC activity by increasing cell surface expression. No additive effect is observed when UBE2E3-CS is coexpressed with an inactive Nedd4-2 mutant, and the stimulatory role of UBE2E3-CS depends on the integrity of the PY motifs (Nedd4-2 binding sites) and the ubiquitination sites on ENaC. In renal mpkCCD(cl4) cells, displaying ENaC-dependent transepithelial Na+ transport, Nedd4-2 and UBE2E3 can be coimmunoprecipitated and overexpression of UBE2E3 affects Na+ transport, corroborating the concept of a concerted action of UBE2E3 and Nedd4-2 in ENaC regulation.
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
Abriel,
Regulation of the cardiac voltage-gated Na+ channel (H1) by the ubiquitin-protein ligase Nedd4.
2000,
Pubmed
,
Xenbase
Anan,
Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes.
1998,
Pubmed
Aristarkhov,
E2-C, a cyclin-selective ubiquitin carrier protein required for the destruction of mitotic cyclins.
1996,
Pubmed
Asher,
Characterization of interactions between Nedd4 and beta and gammaENaC using surface plasmon resonance.
2001,
Pubmed
Asher,
Characterization of the interactions between Nedd4-2, ENaC, and sgk-1 using surface plasmon resonance.
2003,
Pubmed
Auberson,
Epithelial Na+ channel mutants causing Liddle's syndrome retain ability to respond to aldosterone and vasopressin.
2003,
Pubmed
Bens,
Corticosteroid-dependent sodium transport in a novel immortalized mouse collecting duct principal cell line.
1999,
Pubmed
Bull,
Identification of potential diagnostic markers of prostate cancer and prostatic intraepithelial neoplasia using cDNA microarray.
2001,
Pubmed
Chabardès-Garonne,
A panoramic view of gene expression in the human kidney.
2003,
Pubmed
Debonneville,
Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression.
2001,
Pubmed
,
Xenbase
Dinudom,
Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+.
1998,
Pubmed
Dunn,
Domains of the Rsp5 ubiquitin-protein ligase required for receptor-mediated and fluid-phase endocytosis.
2001,
Pubmed
Farr,
Human Nedd4 interacts with the human epithelial Na+ channel: WW3 but not WW1 binds to Na+-channel subunits.
2000,
Pubmed
,
Xenbase
Firsov,
Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: a quantitative approach.
1996,
Pubmed
,
Xenbase
Fotia,
The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels.
2003,
Pubmed
,
Xenbase
Glickman,
The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction.
2002,
Pubmed
Goulet,
Inhibition of the epithelial Na+ channel by interaction of Nedd4 with a PY motif deleted in Liddle's syndrome.
1998,
Pubmed
,
Xenbase
Grossman,
Polyubiquitination of p53 by a ubiquitin ligase activity of p300.
2003,
Pubmed
Hansson,
Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome.
1995,
Pubmed
,
Xenbase
Harvey,
All three WW domains of murine Nedd4 are involved in the regulation of epithelial sodium channels by intracellular Na+.
1999,
Pubmed
Harvey,
The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel.
2001,
Pubmed
Hatakeyama,
Subcellular localization and ubiquitin-conjugating enzyme (E2) interactions of mammalian HECT family ubiquitin protein ligases.
1997,
Pubmed
Helliwell,
Components of a ubiquitin ligase complex specify polyubiquitination and intracellular trafficking of the general amino acid permease.
2001,
Pubmed
Henry,
Affinity and specificity of interactions between Nedd4 isoforms and the epithelial Na+ channel.
2003,
Pubmed
Hershko,
The ubiquitin system.
1998,
Pubmed
Hicke,
Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis.
1996,
Pubmed
Huang,
Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade.
1999,
Pubmed
Huibregtse,
A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase.
1995,
Pubmed
Inoue,
A family with Liddle's syndrome caused by a new missense mutation in the beta subunit of the epithelial sodium channel.
1998,
Pubmed
,
Xenbase
Ito,
cDNA cloning, characterization, and chromosome mapping of UBE2E3 (alias UbcH9), encoding an N-terminally extended human ubiquitin-conjugating enzyme.
1999,
Pubmed
Ito,
N-Terminally extended human ubiquitin-conjugating enzymes (E2s) mediate the ubiquitination of RING-finger proteins, ARA54 and RNF8.
2001,
Pubmed
Kaiser,
A human ubiquitin-conjugating enzyme homologous to yeast UBC8.
1994,
Pubmed
Kamynina,
A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel.
2001,
Pubmed
,
Xenbase
Kamynina,
Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na(+) channel regulation.
2001,
Pubmed
,
Xenbase
Kanelis,
NMR studies of tandem WW domains of Nedd4 in complex with a PY motif-containing region of the epithelial sodium channel.
1998,
Pubmed
Kanelis,
Solution structure of a Nedd4 WW domain-ENaC peptide complex.
2001,
Pubmed
Katzmann,
Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I.
2001,
Pubmed
Kellenberger,
Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure.
2002,
Pubmed
Kellenberger,
Mutations causing Liddle syndrome reduce sodium-dependent downregulation of the epithelial sodium channel in the Xenopus oocyte expression system.
1998,
Pubmed
,
Xenbase
Koegl,
A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly.
1999,
Pubmed
Konstas,
Regulation of the epithelial sodium channel by N4WBP5A, a novel Nedd4/Nedd4-2-interacting protein.
2002,
Pubmed
,
Xenbase
Lott,
A single WW domain is the predominant mediator of the interaction between the human ubiquitin-protein ligase Nedd4 and the human epithelial sodium channel.
2002,
Pubmed
Malik,
Enac degradation in A6 cells by the ubiquitin-proteosome proteolytic pathway.
2001,
Pubmed
,
Xenbase
Matuschewski,
Identification of a novel family of ubiquitin-conjugating enzymes with distinct amino-terminal extensions.
1996,
Pubmed
May,
Early effect of aldosterone on the rate of synthesis of the epithelial sodium channel alpha subunit in A6 renal cells.
1997,
Pubmed
,
Xenbase
McDonald,
Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel.
2002,
Pubmed
Nelson,
A general method of site-specific mutagenesis using a modification of the Thermus aquaticus polymerase chain reaction.
1989,
Pubmed
Nuber,
The ubiquitin-protein ligase E6-associated protein (E6-AP) serves as its own substrate.
1998,
Pubmed
Nuber,
Identification of determinants in E2 ubiquitin-conjugating enzymes required for hect E3 ubiquitin-protein ligase interaction.
1999,
Pubmed
Nuber,
Cloning of human ubiquitin-conjugating enzymes UbcH6 and UbcH7 (E2-F1) and characterization of their interaction with E6-AP and RSP5.
1996,
Pubmed
Pear,
Production of high-titer helper-free retroviruses by transient transfection.
1993,
Pubmed
Pirozzi,
Identification of novel human WW domain-containing proteins by cloning of ligand targets.
1997,
Pubmed
Plafker,
Importin-11, a nuclear import receptor for the ubiquitin-conjugating enzyme, UbcM2.
2000,
Pubmed
Plafker,
Ribosomal protein L12 uses a distinct nuclear import pathway mediated by importin 11.
2002,
Pubmed
Puoti,
Novel isoforms of the beta and gamma subunits of the Xenopus epithelial Na channel provide information about the amiloride binding site and extracellular sodium sensing.
1997,
Pubmed
,
Xenbase
Rotin,
Ubiquitination and endocytosis of plasma membrane proteins: role of Nedd4/Rsp5p family of ubiquitin-protein ligases.
2000,
Pubmed
Schild,
A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system.
1995,
Pubmed
,
Xenbase
Schild,
Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome.
1996,
Pubmed
,
Xenbase
Schwake,
An internalization signal in ClC-5, an endosomal Cl-channel mutated in dent's disease.
2001,
Pubmed
,
Xenbase
Shi,
Interactions of beta and gamma ENaC with Nedd4 can be facilitated by an ERK-mediated phosphorylation.
2002,
Pubmed
,
Xenbase
Shimkets,
Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel.
1994,
Pubmed
Shimkets,
The activity of the epithelial sodium channel is regulated by clathrin-mediated endocytosis.
1997,
Pubmed
,
Xenbase
Snyder,
Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel.
1995,
Pubmed
,
Xenbase
Snyder,
Multiple WW domains, but not the C2 domain, are required for inhibition of the epithelial Na+ channel by human Nedd4.
2001,
Pubmed
,
Xenbase
Snyder,
Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel.
2002,
Pubmed
Soetens,
Ubiquitin is required for sorting to the vacuole of the yeast general amino acid permease, Gap1.
2001,
Pubmed
Staub,
WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome.
1996,
Pubmed
Staub,
Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination.
1997,
Pubmed
,
Xenbase
Tamura,
Liddle disease caused by a missense mutation of beta subunit of the epithelial sodium channel gene.
1996,
Pubmed
,
Xenbase
Vojtek,
Mammalian Ras interacts directly with the serine/threonine kinase Raf.
1993,
Pubmed
