التفاصيل البيبلوغرافية
| العنوان: |
Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. |
| المؤلفون: |
Staub, O., Gautschi, I., Ishikawa, T., Breitschopf, K., Ciechanover, A., Schild, L., Rotin, D. |
| المصدر: |
EMBO Journal; 11/1/97, Vol. 16 Issue 21, p6325-6336, 12p |
| مصطلحات موضوعية: |
SODIUM channels, EPITHELIUM, PROTEINS, UBIQUITIN, HOMEOSTASIS, LYSOSOMES, LIGASES, CELL membranes |
| مستخلص: |
The epithelial Na+ channel (ENaC), composed of three subunits (αβγ), plays a critical role in salt and fluid homeostasis. Abnormalities in channel opening and numbers have been linked to several genetic disorders, including cystic fibrosis, pseudohypoaldosteronism type I and Liddle syndrome. We have recently identified the ubiquitin-protein ligase Nedd4 as an interacting protein of ENaC. Here we show that ENaC is a shortlived protein (t1/2 ∼1 h) that is ubiquitinated in vivo on the α and γ (but not β) subunits. Mutation of a cluster of Lys residues (to Arg) at the N-terminus of γENaC leads to both inhibition of ubiquitination and increased channel activity, an effect augmented by N-terminal Lys to Arg mutations in αENaC, but not in βENaC. This elevated channel activity is caused by an increase in the number of channels present at the plasma membrane; it represents increases in both cell-surface retention or recycling of ENaC and incorporation of new channels at the plasma membrane, as determined by Brefeldin A treatment. In addition, we find that the rapid turnover of the total pool of cellular ENaC is attenuated by inhibitors of both the proteasome and the lysosomal/endosomal degradation systems, and propose that whereas the unassembled subunits are degraded by the proteasome, the assembled αβγENaC complex is targeted for lysosomal degradation. Our results suggest that ENaC function is regulated by ubiquitination, and propose a paradigm for ubiquitinationmediated regulation of ion channels. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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