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Regulation of transepithelial NA+ transport in the distal bephron by ubiquitination and de-ubiquitination

English title Regulation of transepithelial NA+ transport in the distal bephron by ubiquitination and de-ubiquitination
Applicant Staub Olivier
Number 103779
Funding scheme Project funding
Research institution Département de Pharmacologie & Toxicologie Faculté de Biologie et de Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Cardiovascular Research
Start/End 01.04.2004 - 31.03.2009
Approved amount 776'445.00
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All Disciplines (2)

Discipline
Cardiovascular Research
Cellular Biology, Cytology

Keywords (6)

Sodium transport; channels; kidney; post-translational modification; ubiquitin; de-ubiquitination

Lay Summary (English)

Lead
Lay summary
1. Background
Excess salt intake is a major risk factor for hypertension. Finaladjustment of Na+ balance in extracellular fluids (including the blood) isachieved by regulated Na+ transport in the aldosterone sensitive distalnephron (ASDN). Na+ transport occurring in this part of the nephroninvolves the activity of the epithelial Na+ channel ENaC, which isregulated by a number of hormonal pathways, including aldosterone,vasopressin and insulin. We have shown that some of these regulatorypathways involve modulation of ubiquitination (a form of post-translational modification) of the ENaC channel. Briefly, we havedemonstrated that the ubiquitin-protein ligase Nedd4-2 binds to andubiquitinates ENaC, thereby marking it for rapid internalization. We haveestablished that this mechanism is impaired in Liddle's syndrome, aninherited form of salt-sensitive hypertension, in which mutations in theENaC genes lead to the truncation/deletion of the Nedd4-2 binding sites,and subsequently to the loss of interaction with Nedd4-2 and accumulationof the protein at the cell surface. The interaction between Nedd4-2 andENaC is regulated by the aldosterone-inducible Sgk1 kinase, whichphosphorylates Nedd4-2, leading to a reduction of Nedd4-2/ENaCinteraction, and consequently an increase of ENaC channels at the cellsurface. In recent years, it has become increasingly clear, thatubiquitination is a reversible process, which involves the activity ofso-called de-ubiquitinating enzymes, or DUBs.

2.General objective
Our general objective is to elucidate and characterize the regulatorymechanisms that control the cell surface expression of ion channels viaubiquitination, and de-ubiquitination. We hypothesize that thesemechanisms are regulated by the balance of Nedd4-2 dependantubiquitination and DUB dependant de-ubiquitination of ENaC or of otherrelevant substrates.

3.Methods
We will study these questions both in vitro in renal epithelial celllines, and in vivo in transgenic mouse models. We will focus on the roleof Nedd4-2 and Sgk1, and we will identify and study possible DUBsimportant for the regulation of the transepithelial Na+ transport.

4. Expected value of project
The project addresses not only fundamental questions with respect to thephysiological regulation of renal Na+ transport (and its consequences forthe maintenance of blood pressure), but treats also novel cell biologicalissues with respect to mechanisms implicatingubiquitination/deubiquitination in the control of plasma membraneproteins, and in particular of ion channels.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
125422 Regulation of epithelial Na(+) transport: implication of controlled ubiquitylation and ER-associated degradation 01.04.2009 Project funding
141013 Integrated kinase and ubiquitylation networks coordinating balanced Na+ homeostasis and blood pressure regulation by the kidney 01.04.2012 Project funding
141013 Integrated kinase and ubiquitylation networks coordinating balanced Na+ homeostasis and blood pressure regulation by the kidney 01.04.2012 Project funding
64052 Regulation of surface expression of ion channels by the ubiqui- tin-protein ligase Nedd4 01.04.2001 Project funding

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