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GRK6 phosphorylates IκBα at Ser(32)/Ser(36) and enhances TNF-α-induced inflammation.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2015 May 29; Vol. 461 (2), pp. 307-13. Date of Electronic Publication: 2015 Apr 13. - Publication Year :
- 2015
-
Abstract
- G protein-coupled receptor kinases (GRKs) comprise a family of seven serine/threonine kinases that phosphorylate agonist-activated G protein-coupled receptors (GPCRs). It has recently been reported that GRKs regulate GPCR-independent signaling through the phosphorylation of intracellular proteins. To date, several intracellular substrates for GRK2 and GRK5 have been reported. However, those for GRK6 are poorly understood. Here we identified IκBα, a negative regulator of NF-κB signaling, as a substrate for GRK6. GRK6 directly phosphorylated IκBα at Ser(32)/Ser(36), and the kinase activity of GRK6 was required for the promotion of NF-κB signaling after TNF-α stimulation. Knockout of GRK6 in peritoneal macrophages remarkably attenuated the transcription of inflammatory genes after TNF-α stimulation. In addition, we developed a bioluminescence resonance energy transfer (BRET) probe to monitor GRK6 activity. Using this probe, we revealed that the conformational change of GRK6 was induced by TNF-α. In summary, our study demonstrates that TNF-α induces GRK6 activation, and GRK6 promotes inflammatory responses through the phosphorylation of IκBα.<br /> (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cells, Cultured
G-Protein-Coupled Receptor Kinases chemistry
G-Protein-Coupled Receptor Kinases genetics
G-Protein-Coupled Receptor Kinases metabolism
Gene Knockdown Techniques
Gene Knockout Techniques
I-kappa B Proteins chemistry
I-kappa B Proteins metabolism
Inflammation metabolism
Mice
Mice, Inbred C57BL
NF-KappaB Inhibitor alpha
NF-kappa B immunology
NIH 3T3 Cells
Phosphorylation
Protein Conformation
G-Protein-Coupled Receptor Kinases immunology
I-kappa B Proteins immunology
Inflammation immunology
Tumor Necrosis Factor-alpha immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2104
- Volume :
- 461
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 25881508
- Full Text :
- https://doi.org/10.1016/j.bbrc.2015.04.027