Hrs Controls Sorting of the Epithelial Na+ Channel between Endosomal Degradation and Recycling Pathways

Ruifeng Zhou; Rajesh Kabra; Diane R Olson; Robert C Piper; Peter M Snyder

doi:10.1074/jbc.M110.150755

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Hrs Controls Sorting of the Epithelial Na+ Channel between Endosomal Degradation and Recycling Pathways

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Hrs Controls Sorting of the Epithelial Na+ Channel between Endosomal Degradation and Recycling Pathways

Ruifeng Zhou, Rajesh Kabra, Diane R Olson, Robert C Piper and Peter M Snyder

The Journal of biological chemistry, Vol.285(40), pp.30523-30530

10/01/2010

DOI: 10.1074/jbc.M110.150755

PMCID: PMC2945546

PMID: 20675381

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Abstract

Epithelial Na + absorption is regulated by Nedd4-2, an E3 ubiquitin 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 functions through two distinct effects on trafficking, enhancing both ENaC endocytosis and ENaC degradation in lysosomes. To investigate the mechanism by which Nedd4-2 targets ENaC to lysosomes, we tested the role of hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a component of the endosomal sorting complexes required for transport (ESCRT)-0 complex. We found that α-, β-, and γENaC each interact with Hrs. These interactions were enhanced by Nedd4-2 and were dependent on the catalytic function of Nedd4-2 as well as its WW domains. Mutation of ENaC PY motifs, responsible for inherited hypertension (Liddle syndrome), decreased Hrs binding to ENaC. Moreover, binding of ENaC to Hrs was reduced by dexamethasone/serum- and glucocorticoid-inducible kinase and cAMP, which are signaling pathways that inhibit Nedd4-2. Nedd4-2 bound to Hrs and catalyzed Hrs ubiquitination but did not alter Hrs protein levels. Expression of a dominant negative Hrs lacking its ubiquitin-interacting motif (Hrs-ΔUIM) increased ENaC surface expression and current. This occurred through reduced degradation of the cell surface pool of proteolytically activated ENaC, which enhanced its recycling to the cell surface. In contrast, Hrs-ΔUIM had no effect on degradation of uncleaved inactive channels. The data support a model in which Nedd4-2 induces binding of ENaC to Hrs, which mediates the sorting decision between ENaC degradation and recycling.

Hypertension

E3 Ubiquitin Ligase

Protein Sorting

Amiloride

Ion Channels

Cell Surface Protein

Membrane Biology

Trafficking

Protein Synthesis and Degradation

Sodium Channels

ENaC

Protein-Protein Interactions

Details

Title: Subtitle: Hrs Controls Sorting of the Epithelial Na+ Channel between Endosomal Degradation and Recycling Pathways
Creators: Ruifeng Zhou - From the Departments of
Rajesh Kabra - From the Departments of
Diane R Olson - From the Departments of
Robert C Piper - Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
Peter M Snyder - From the Departments of
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.285(40), pp.30523-30530
DOI: 10.1074/jbc.M110.150755
PMID: 20675381
PMCID: PMC2945546
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
Grant note: HL058812 / National Institutes of Health
Alternative title: ENaC Sorting by Hrs
Language: English
Date published: 10/01/2010
Academic Unit: Molecular Physiology and Biophysics; Cardiovascular Medicine; Medicine Administration; Internal Medicine
Record Identifier: 9984025577002771

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