Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel

Nandita S Raikwar; Christie P Thomas

doi:10.1152/ajprenal.00339.2007

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Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel

Journal article

Open access

Peer reviewed

Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel

Nandita S Raikwar and Christie P Thomas

American journal of physiology. Renal physiology, Vol.294(5), pp.F1157-1165

05/2008

DOI: 10.1152/ajprenal.00339.2007

PMCID: PMC2424110

PMID: 18322022

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Abstract

We previously reported the existence of multiple isoforms of human Nedd4-2 (Am J Physiol Renal Physiol 285: F916-F929, 2003). When overexpressed in M-1 collecting duct epithelia, full-length Nedd4-2 (Nedd4-2), Nedd4-2 lacking the NH(2)-terminal C2 domain (Nedd4-2DeltaC2), and Nedd4-2 lacking WW domains 2 and 3 (Nedd4-2DeltaWW2,3) variably reduce benzamil-sensitive Na(+) transport. We investigated the effect of each of the Nedd4-2 isoforms on cell surface expression and ubiquitination of ENaC subunits. We find that alphaENaC when transfected alone or with beta and gammaENaC is expressed at the cell surface and this membrane expression is variably reduced by coexpression with each of the Nedd4-2 isoforms. Nedd4-2 reduces the half-life of ENaC subunits and enhances the ubiquitination of alpha, beta, and gammaENaC subunits when expressed alone or together suggesting that each subunit is a target for Nedd4-2-mediated ubiquitination. As has been reported recently, we confirm that the surface-expressed pool of ENaC is multi-ubiquitinated. Inhibitors of the proteasome increase ubiquitination of ENaC subunits and stimulate Na(+) transport in M-1 cells consistent with a role for the ubiquitin-proteasome pathway in regulating Na(+) transport in the collecting duct.

Kidney Tubules, Collecting - drug effects

Cell Line

Epithelium - drug effects

Epithelium - metabolism

Endosomal Sorting Complexes Required for Transport

Humans

Ubiquitin - metabolism

Ubiquitin-Protein Ligases - metabolism

Half-Life

Epithelial Sodium Channels - biosynthesis

Epithelial Sodium Channels - metabolism

Sodium - metabolism

Kidney Tubules, Collecting - cytology

Isomerism

Kidney Tubules, Collecting - metabolism

Transfection

Epithelial Sodium Channels - drug effects

Adenoviridae - genetics

Nedd4 Ubiquitin Protein Ligases

Receptors, Cell Surface - biosynthesis

Kinetics

Genetic Vectors

Ubiquitin-Protein Ligases - genetics

Details

Title: Subtitle: Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel
Creators: Nandita S Raikwar - Department of Internal Medicine, E300 GH, University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Christie P Thomas
Resource Type: Journal article
Publication Details: American journal of physiology. Renal physiology, Vol.294(5), pp.F1157-1165
DOI: 10.1152/ajprenal.00339.2007
PMID: 18322022
PMCID: PMC2424110
NLM abbreviation: Am J Physiol Renal Physiol
ISSN: 1931-857X
eISSN: 1522-1466
Publisher: United States
Grant note: HL-71664 / NHLBI NIH HHS R01 HL071664-05 / NHLBI NIH HHS R01 HL071664 / NHLBI NIH HHS
Language: English
Date published: 05/2008
Academic Unit: Stead Family Department of Pediatrics; Obstetrics and Gynecology; Internal Medicine
Record Identifier: 9983985905502771

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