The Deubiquitinating Enzyme UCH-L3 Regulates the Apical Membrane Recycling of the Epithelial Sodium Channel

Butterworth, Michael; Edinger, Robert S.; Ovaa, Huib; Burg, Danny; Johnson, John P.; Frizzell, Raymond A.

doi:10.1074/jbc.m707989200

Cited by 95 publications

(62 citation statements)

References 38 publications

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“…75,78 The target sequences for all siRNA constructs are listed in Supplemental Table 1. For miRNA overexpression, plasmids containing the stem-loop pre-miR sequences for mature miRs 335-3p, 1983 and 290-5p were obtained from GeneCopoeia (Rockville, MD) along with scrambled control clones.…”

Section: Short-circuit Current Recordingsmentioning

confidence: 99%

Aldosterone Regulates MicroRNAs in the Cortical Collecting Duct to Alter Sodium Transport

Edinger

Coronnello²,

Bodnar³

et al. 2014

Journal of the American Society of Nephrology

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A role for microRNAs (miRs) in the physiologic regulation of sodium transport in the kidney has not been established. In this study, we investigated the potential of aldosterone to alter miR expression in mouse cortical collecting duct (mCCD) epithelial cells. Microarray studies demonstrated the regulation of miR expression by aldosterone in both cultured mCCD and isolated primary distal nephron principal cells. Aldosterone regulation of the most significantly downregulated miRs, mmu-miR-335-3p, mmu-miR-290-5p, and mmu-miR-1983 was confirmed by quantitative RT-PCR. Reducing the expression of these miRs separately or in combination increased epithelial sodium channel (ENaC)-mediated sodium transport in mCCD cells, without mineralocorticoid supplementation. Artificially increasing the expression of these miRs by transfection with plasmid precursors or miR mimic constructs blunted aldosterone stimulation of ENaC transport. Using a newly developed computational approach, termed ComiR, we predicted potential gene targets for the aldosterone-regulated miRs and confirmed ankyrin 3 (Ank3) as a novel aldosterone and miR-regulated protein.A dual-luciferase assay demonstrated direct binding of the miRs with the Ank3-39 untranslated region. Overexpression of Ank3 increased and depletion of Ank3 decreased ENaC-mediated sodium transport in mCCD cells. These findings implicate miRs as intermediaries in aldosterone signaling in principal cells of the distal kidney nephron.

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Section: Short-circuit Current Recordingsmentioning

confidence: 99%

Aldosterone Regulates MicroRNAs in the Cortical Collecting Duct to Alter Sodium Transport

Edinger

Coronnello²,

Bodnar³

et al. 2014

Journal of the American Society of Nephrology

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“…Once internalized, channels may be targeted for degradation (11)(12)(13). Alternatively, the release of ubiquitin by deubiquitinating enzymes allows channels to recycle to the plasma membrane (14). Loss of the Pro-Tyr motif leads to increased channel surface expression and channel processing by proteases that enhance its activity (see below).…”

Section: Role Of Na ؉ In the Control Of Blood Pressurementioning

confidence: 99%

Role of Epithelial Sodium Channels and Their Regulators in Hypertension

Soundararajan

Pearce

Hughey

et al. 2010

Journal of Biological Chemistry

105

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The kidney has a central role in the regulation of blood pressure, in large part through its role in the regulated reabsorption of filtered Na ؉ . Epithelial Na ؉ channels (ENaCs) are expressed in the most distal segments of the nephron and are a target of volume regulatory hormones. A variety of factors regulate ENaC activity, including several aldosterone-induced proteins that are present within an ENaC regulatory complex. Proteases also regulate ENaC by cleaving the channel and releasing intrinsic inhibitory tracts. Polymorphisms or mutations within channel subunits or regulatory pathways that enhance channel activity may contribute to an increase in blood pressure in individuals with essential hypertension.

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“…Isolation of Early Endosomes-To determine if USP10 is expressed in early endosomes, differential centrifugation and fractionation techniques were used to isolate early endosomes from CFBE cells using a protocol adapted from Butterworth et al (9). Briefly, polarized CFBE cells, grown on 24-mm permeable membrane supports, were scraped into phosphate-buffered saline, pelleted, and resuspended in 600 l of HEPES buffer (250 mM sucrose, 10 mM HEPES, 0.5 mM EDTA at pH 7.4 containing protease inhibitors (Roche Applied Science)).…”

Section: Methodsmentioning

confidence: 99%

The Deubiquitinating Enzyme USP10 Regulates the Post-endocytic Sorting of Cystic Fibrosis Transmembrane Conductance Regulator in Airway Epithelial Cells

Bomberger

Barnaby

Stanton

2009

Journal of Biological Chemistry

102

117

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The cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ABC transporter superfamily, is a cyclic AMP-regulated chloride channel and a regulator of other ion channels and transporters. In epithelial cells CFTR is rapidly endocytosed from the apical plasma membrane and efficiently recycles back to the plasma membrane. Because ubiquitination targets endocytosed CFTR for degradation in the lysosome, deubiquitinating enzymes (DUBs) are likely to facilitate CFTR recycling. Accordingly, the aim of this study was to identify DUBs that regulate the post-endocytic sorting of CFTR. Using an activity-based chemical screen to identify active DUBs in human airway epithelial cells, we demonstrated that Ubiquitin Specific Protease-10 (USP10) is located in early endosomes and regulates the deubiquitination of CFTR and its trafficking in the post-endocytic compartment. small interference RNA-mediated knockdown of USP10 increased the amount of ubiquitinated CFTR and its degradation in lysosomes, and reduced both apical membrane CFTR and CFTR-mediated chloride secretion. Moreover, a dominant negative USP10 (USP10-C424A) increased the amount of ubiquitinated CFTR and its degradation, whereas overexpression of wt-USP10 decreased the amount of ubiquitinated CFTR and increased the abundance of CFTR. These studies demonstrate a novel function for USP10 in facilitating the deubiquitination of CFTR in early endosomes and thereby enhancing the endocytic recycling of CFTR.

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The Deubiquitinating Enzyme UCH-L3 Regulates the Apical Membrane Recycling of the Epithelial Sodium Channel

Cited by 95 publications

References 38 publications

Aldosterone Regulates MicroRNAs in the Cortical Collecting Duct to Alter Sodium Transport

Aldosterone Regulates MicroRNAs in the Cortical Collecting Duct to Alter Sodium Transport

Role of Epithelial Sodium Channels and Their Regulators in Hypertension

The Deubiquitinating Enzyme USP10 Regulates the Post-endocytic Sorting of Cystic Fibrosis Transmembrane Conductance Regulator in Airway Epithelial Cells

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