Ubiquitin-specific Peptidase 8 (USP8) Regulates Endosomal Trafficking of the Epithelial Na+ Channel

Ruifeng Zhou; Vivian R Tomkovicz; Phillip L Butler; Luis A Ochoa; Zerubbabel J Peterson; Peter M Snyder

doi:10.1074/jbc.M112.425272

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Ubiquitin-specific Peptidase 8 (USP8) Regulates Endosomal Trafficking of the Epithelial Na+ Channel

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Ubiquitin-specific Peptidase 8 (USP8) Regulates Endosomal Trafficking of the Epithelial Na+ Channel

Ruifeng Zhou, Vivian R Tomkovicz, Phillip L Butler, Luis A Ochoa, Zerubbabel J Peterson and Peter M Snyder

The Journal of biological chemistry, Vol.288(8), pp.5389-5397

02/22/2013

DOI: 10.1074/jbc.M112.425272

PMCID: PMC3581384

PMID: 23297398

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Abstract

Background: Ubiquitination controls trafficking of the epithelial Na + channel (ENaC) in the endocytic pathway. Results: USP8 deubiquitinated ENaC and blocked its degradation, resulting in increased ENaC abundance at the cell surface and increased current. Conclusion: USP8 regulates endocytic sorting of ENaC. Significance: Regulation of the ubiquitination state of ENaC is important for Na + homeostasis and blood pressure control. Ubiquitination plays a key role in trafficking of the epithelial Na + channel (ENaC). Previous work indicated that ubiquitination enhances ENaC endocytosis and sorting to lysosomes for degradation. Moreover, a defect in ubiquitination causes Liddle syndrome, an inherited form of hypertension. In this work, we identified a role for USP8 in the control of ENaC ubiquitination and trafficking. USP8 increased ENaC current in Xenopus oocytes and collecting duct epithelia and enhanced ENaC abundance at the cell surface in HEK 293 cells. This resulted from altered endocytic sorting; USP8 abolished ENaC degradation in the endocytic pathway, but it had no effect on ENaC endocytosis. USP8 interacted with ENaC, as detected by co-immunoprecipitation, and it deubiquitinated ENaC. Consistent with a functional role for deubiquitination, mutation of the cytoplasmic lysines of ENaC reduced the effect of USP8 on ENaC cell surface abundance. In contrast to USP8, USP2-45 increased ENaC surface abundance by reducing endocytosis but not degradation. Thus, USP8 and USP2-45 selectively modulate ENaC trafficking at different steps in the endocytic pathway. Together with previous work, the data indicate that the ubiquitination state of ENaC is critical for the regulation of epithelial Na + absorption.

Hypertension

Protein Sorting

Endocytosis

Amiloride

Membrane Biology

Deubiquitination

Ubiquitin-dependent Protease

Epithelial Cell

ENaC

Details

Title: Subtitle: Ubiquitin-specific Peptidase 8 (USP8) Regulates Endosomal Trafficking of the Epithelial Na+ Channel
Creators: Ruifeng Zhou - From the Departments of
Vivian R Tomkovicz - From the Departments of
Phillip L Butler - From the Departments of
Luis A Ochoa - Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242
Zerubbabel J Peterson - From the Departments of
Peter M Snyder - From the Departments of
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.288(8), pp.5389-5397
DOI: 10.1074/jbc.M112.425272
PMID: 23297398
PMCID: PMC3581384
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; HL072256 / National Institutes of Health
Alternative title: USP8 Regulates ENaC Trafficking
Language: English
Date published: 02/22/2013
Academic Unit: Molecular Physiology and Biophysics; Cardiology; Stead Family Department of Pediatrics; Cardiovascular Medicine; Medicine Administration; Internal Medicine
Record Identifier: 9984025364902771

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