Nedd4-2 catalyzes ubiquitination and degradation of cell surface ENaC

Ruifeng Zhou; Saumil V Patel; Peter M Snyder

doi:10.1074/jbc.M611329200

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Nedd4-2 catalyzes ubiquitination and degradation of cell surface ENaC

Journal article

Open access

Peer reviewed

Nedd4-2 catalyzes ubiquitination and degradation of cell surface ENaC

Ruifeng Zhou, Saumil V Patel and Peter M Snyder

The Journal of biological chemistry, Vol.282(28), pp.20207-20212

07/13/2007

DOI: 10.1074/jbc.M611329200

PMID: 17502380

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Abstract

Epithelial Na(+) absorption is regulated by Nedd4-2, an E3 ubiquitin-protein ligase that reduces expression of the epithelial Na(+) channel ENaC at the cell surface. Defects in this regulation cause Liddle syndrome, an inherited form of hypertension. Previous work found that Nedd4-2 binds to ENaC via PY motifs located in the C termini of alpha-, beta-, and gammaENaC. However, little is known about the mechanism by which Nedd4-2 regulates ENaC surface expression. Here we found that Nedd4-2 catalyzes ubiquitination of alpha-, beta-, and gammaENaC; Nedd4-2 overexpression increased ubiquitination, whereas Nedd4-2 silencing decreased ubiquitination. Although Nedd4-2 increased both mono/oligoubiquitinated and multiubiquitinated forms of ENaC, monoubiquitination was sufficient for Nedd4-2 to reduce ENaC surface expression and reduce ENaC current. Ubiquitination was disrupted by Liddle syndrome-associated mutations in ENaC or mutation of the catalytic HECT domain in Nedd4-2. Several findings suggest that the interaction between Nedd4-2 and ENaC is localized to the cell surface. First, Nedd4-2 bound to a population of ENaC at the cell surface. Second, Nedd4-2 catalyzed ubiquitination of cell surface ENaC. Third, Nedd4-2 selectively reduced ENaC expression at the cell surface but did not alter the quantity of immature ENaC in the biosynthetic pathway. Finally, Nedd4-2 induced degradation of the cell surface pool of ENaC. Together, the data suggest a model in which Nedd4-2 binds to and ubiquitinates ENaC at the cell surface, which targets surface ENaC for degradation, and thus, reduces epithelial Na(+) transport.

Cell Line

Endosomal Sorting Complexes Required for Transport

Humans

Gene Silencing

Ubiquitin - metabolism

Ubiquitin-Protein Ligases - metabolism

Cell Membrane - genetics

Epithelial Sodium Channels - metabolism

Sodium - metabolism

Protein Processing, Post-Translational - physiology

Amino Acid Motifs - physiology

Epithelial Sodium Channels - genetics

Models, Biological

Nedd4 Ubiquitin Protein Ligases

Cell Membrane - metabolism

Mutation

Ion Transport - physiology

Ubiquitin-Protein Ligases - genetics

Protein Binding - physiology

Protein Structure, Tertiary - physiology

Details

Title: Subtitle: Nedd4-2 catalyzes ubiquitination and degradation of cell surface ENaC
Creators: Ruifeng Zhou - Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, IA 52242, USA
Saumil V Patel
Peter M Snyder
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.282(28), pp.20207-20212
DOI: 10.1074/jbc.M611329200
PMID: 17502380
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Language: English
Date published: 07/13/2007
Academic Unit: Molecular Physiology and Biophysics; Cardiovascular Medicine; Medicine Administration; Internal Medicine
Record Identifier: 9984025693302771

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