Early transcriptional control of ENaC (de)ubiquitylation by aldosterone.
Aldosterone increases sodium reabsorption across kidney target tubules already before it increases the number of transport proteins, indicating that the early functional response to aldosterone depends on the activation of preexisting channels and pumps. A central mediator of this action is the early aldosterone-induced kinase Sgk1 that de-represses the surface expression and activity of the epithelial sodium channel (ENaC). A main mechanism by which Sgk1 exerts this de-repression is the phosphorylation of the ubiquitin ligase Nedd4-2 that is thereby prevented from ubiquitylating ENaC. Among a series of new early aldosterone-induced gene products recently identified in kidney target tubules, an additional regulator of ENaC ubiquitylation, the deubiquitylating enzyme Usp2-45, was identified. Coexpression of Usp2-45 was shown to increase ENaC surface expression and activity, and to decrease its ubiquitylation in expression systems, whereas other Usps such as the splice variant Usp2-69 had no effect. Since both Sgk1 and Usp2-45 are similarly induced in distal colon as well, in contrast to other gene products strongly induced in kidney that are not regulated in colon, we suggest that (de)ubiquitylation is the major ENaC regulatory mechanism targeted by aldosterone in the short-term via transcriptional regulation.
Verrey
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F
Institute of Physiology and Centre for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland. verrey@access.unizh.ch
Fakitsas
P
P
Adam
G
G
Staub
O
O
D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D010450:Endopeptidases / Q000235:genetics*; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D017136:Ion Transport / Q000235:genetics; D007684:Kidney Tubules / Q000378:metabolism*; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases; D014452:Ubiquitins / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
D000450:Aldosterone; D010450:Endopeptidases; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases; D064570:Ubiquitin-Specific Proteases; D014452:Ubiquitins; D000099184:Serum-Glucocorticoid Regulated Kinases; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human; C000618461:Nedd4l protein, mouse; C579224:Usp2 protein, mouse