The human ENaC (epithelial sodium channel), a complex of three subunits, provides the rate-limiting step for sodium uptake in the distal nephron, and therefore plays a key role in salt homoeostasis and in regulating blood pressure. The number of active sodium channel complexes present at the plasma membrane appears to be tightly controlled. In Liddle's syndrome, a form of hypertension caused by an increase in the number of active sodium channels at the cell membrane, the βENaC or γENaC subunit gene contains a mutation that disrupts the binding site for the Nedd4 (neuronal precursor cell expressed developmentally down-regulated gene 4) family of ubiquitin-protein ligases. Therefore ubiquitination of channel subunits may be involved in altering cell surface ENaC. Here, we provide evidence that the ENaC subunits located at the cell surface are modified with multiple mono-ubiquitins (multi-ubiquitination) and that Nedd4-2 modulates this ubiquitination. We confirm that ENaC is associated with the μ2 subunit of the AP-2 (adaptor protein 2) clathrin adaptor. Since mono- or multi-ubiquitination of other membrane proteins is a signal for their internalization by clathrin-mediated endocytosis and subsequent trafficking, our results support a model whereby ubiquitin and clathrin adaptor binding sites act in concert to remove ENaC from the cell surface.
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Research Article|
June 13 2007
Epithelial sodium channel (ENaC) is multi-ubiquitinated at the cell surface
Dominik Wiemuth;
Dominik Wiemuth
1
1Department of Physiology, University of Otago, PO Box 913, Dunedin 9054, New Zealand
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Ying Ke;
Ying Ke
1Department of Physiology, University of Otago, PO Box 913, Dunedin 9054, New Zealand
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Meino Rohlfs;
Meino Rohlfs
2
1Department of Physiology, University of Otago, PO Box 913, Dunedin 9054, New Zealand
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Fiona J. Mc Donald
Fiona J. Mc Donald
3
1Department of Physiology, University of Otago, PO Box 913, Dunedin 9054, New Zealand
3To whom correspondence should be addressed (email fiona.mcdonald@stonebow.otago.ac.nz).
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Publisher: Portland Press Ltd
Received:
May 22 2006
Revision Received:
February 14 2007
Accepted:
March 23 2007
Accepted Manuscript online:
March 23 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2007 Biochemical Society
2007
Biochem J (2007) 405 (1): 147–155.
Article history
Received:
May 22 2006
Revision Received:
February 14 2007
Accepted:
March 23 2007
Accepted Manuscript online:
March 23 2007
Citation
Dominik Wiemuth, Ying Ke, Meino Rohlfs, Fiona J. Mc Donald; Epithelial sodium channel (ENaC) is multi-ubiquitinated at the cell surface. Biochem J 1 July 2007; 405 (1): 147–155. doi: https://doi.org/10.1042/BJ20060747
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