Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action.

Details

Serval ID
serval:BIB_689620E22F3F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action.
Journal
The Journal of clinical investigation
Author(s)
Roy A., Al-Qusairi L., Donnelly B.F., Ronzaud C., Marciszyn A.L., Gong F., Chang Y.P., Butterworth M.B., Pastor-Soler N.M., Hallows K.R., Staub O., Subramanya A.R.
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Publication state
Published
Issued date
09/2015
Peer-reviewed
Oui
Volume
125
Number
9
Pages
3433-3448
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
Publication Status: ppublish
Abstract
The thiazide-sensitive NaCl cotransporter (NCC) is important for renal salt handling and blood-pressure homeostasis. The canonical NCC-activating pathway consists of With-No-Lysine (WNK) kinases and their downstream effector kinases SPAK and OSR1, which phosphorylate NCC directly. The upstream mechanisms that connect physiological stimuli to this system remain obscure. Here, we have shown that aldosterone activates SPAK/OSR1 via WNK1. We identified 2 alternatively spliced exons embedded within a proline-rich region of WNK1 that contain PY motifs, which bind the E3 ubiquitin ligase NEDD4-2. PY motif-containing WNK1 isoforms were expressed in human kidney, and these isoforms were efficiently degraded by the ubiquitin proteasome system, an effect reversed by the aldosterone-induced kinase SGK1. In gene-edited cells, WNK1 deficiency negated regulatory effects of NEDD4-2 and SGK1 on NCC, suggesting that WNK1 mediates aldosterone-dependent activity of the WNK/SPAK/OSR1 pathway. Aldosterone infusion increased proline-rich WNK1 isoform abundance in WT mice but did not alter WNK1 abundance in hypertensive Nedd4-2 KO mice, which exhibit high baseline WNK1 and SPAK/OSR1 activity toward NCC. Conversely, hypotensive Sgk1 KO mice exhibited low WNK1 expression and activity. Together, our findings indicate that the proline-rich exons are modular cassettes that convert WNK1 into a NEDD4-2 substrate, thereby linking aldosterone and other NEDD4-2-suppressing antinatriuretic hormones to NCC phosphorylation status.
Keywords
Aldosterone/pharmacology, Alternative Splicing/drug effects, Alternative Splicing/physiology, Animals, Endosomal Sorting Complexes Required for Transport/genetics, Endosomal Sorting Complexes Required for Transport/metabolism, Enzyme Activation/drug effects, Enzyme Activation/physiology, Gene Expression Regulation, Enzymologic/drug effects, Gene Expression Regulation, Enzymologic/physiology, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins/biosynthesis, Intracellular Signaling Peptides and Proteins/genetics, Mice, Mice, Knockout, Minor Histocompatibility Antigens, Nedd4 Ubiquitin Protein Ligases, Protein Serine-Threonine Kinases/biosynthesis, Protein Serine-Threonine Kinases/genetics, Protein Serine-Threonine Kinases/metabolism, Signal Transduction/drug effects, Signal Transduction/physiology, Ubiquitin-Protein Ligases/genetics, Ubiquitin-Protein Ligases/metabolism, WNK Lysine-Deficient Protein Kinase 1
Pubmed
Web of science
Open Access
Yes
Create date
03/11/2015 19:44
Last modification date
30/04/2024 7:05
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