Phosphorylation of Farnesoid X Receptor at Serine 154 Links Ligand Activation With Degradation

Published on Aug 29, 2016in Molecular Endocrinology3.628
· DOI :10.1210/ME.2016-1105
Takuyu Hashiguchi2
Estimated H-index: 2
(NIH: National Institutes of Health),
Shingo Arakawa1
Estimated H-index: 1
(NIH: National Institutes of Health)
+ 3 AuthorsMasahiko Negishi64
Estimated H-index: 64
(NIH: National Institutes of Health)
Comparison of 11 human nuclear receptor amino acid sequences revealed a conserved phosphorylation motif within their DNA-binding domains as an intramolecular signal that regulates proteolytic degradation. Nuclear receptors use this signal to either degrade or proscribe degradation through either the proteasome or nonproteasome pathways. A phosphomimetic farnesoid X receptor (FXR) S154D mutant neither bound to nor trans-activated an FXR-response element-driven reporter gene and was rapidly degraded in COS-1 cells. Ectopically expressed FXR had increased Ser154 phosphorylation in COS-1 cells after ligand treatment, and knock-down of the nuclear vaccinia-related kinase 1 (VRK1) greatly reduced this phosphorylation. FXR was phosphorylated at Ser154 in the nucleus of centrilobular hepatocytes only in ligand-treated mice. Thus, FXR Ser154 phosphorylation is a rheostat for activation and subsequent degradation that controls receptor levels and activity.
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