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Regulation of the delta and alpha epithelial sodium channel (ENaC) by ubiquitination and Nedd8
Author(s) -
Ly Kevin,
McIntosh C. Joy,
Biasio Wolfgang,
Liu Yongfeng,
Ke Ying,
Olson Diane R.,
Miller John H.,
Page Rachel,
Snyder Peter M.,
McDonald Fiona J.
Publication year - 2013
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24390
Subject(s) - epithelial sodium channel , ubiquitin , ubiquitin ligase , amiloride , nedd4 , chemistry , microbiology and biotechnology , sodium channel , ion channel , biochemistry , biology , sodium , receptor , organic chemistry , gene
The δ epithelial sodium channel (δENaC) is a proton‐activated, sodium‐selective, amiloride‐sensitive ion channel in the ENaC/degenerin family of ion channels involved in blood pressure regulation and mechanosensation. Other ENaC family members are subject to ubiquitin modification leading to internalization from the cell surface, and degradation of the channel. Here, we show that δENaC is also modified by ubiquitin on three intracellular lysine residues. Absence of these lysines abolished ubiquitin modification of δENaC and increased cell surface levels of δENaC. Although the HECT‐domain ubiquitin ligase Nedd4‐2 reduced amiloride‐sensitive current generated by δβγENaC‐containing channels, δENaC does not contain a binding site for Nedd4‐2; therefore, this effect is probably mediated by the βγENaC subunits. Nedd8, a ubiquitin‐like protein that regulates RING‐domain E3 ubiquitin ligases, promoted δENaC ubiquitination, decreased both the intracellular and cell surface δENaC populations, and decreased δβγENaC amiloride‐sensitive short circuit current (I sc ‐amiloride) in a mammalian epithelium. Nedd8 also promoted α− and γENaC ubiquitination, decreased the cell surface pools, and decreased αβγENaC I sc ‐amiloride. Conversely, XIAP, a single subunit RING E3 ligase, decreased ubiquitinated δENaC, increased the δENaC cell surface pool and increased δβγENaC I sc ‐amiloride. Therefore δ− and α − βγENaC channel function may be influenced by RING‐domain E3 ubiquitin ligases. J. Cell. Physiol. 228: 2190–2201, 2013. © 2013 Wiley Periodicals, Inc.