Abstract
The glucocorticoid (GC) receptor (GR) suppresses inflammation by activating anti-inflammatory and repressing pro-inflammatory genes. GR-interacting protein-1 (GRIP1) is a GR corepressor in macrophages, however, whether GRIP1 mediates GR-activated transcription, and what dictates its coactivator versus corepressor properties is unknown. Here we report that GRIP1 loss in macrophages attenuates glucocorticoid induction of several anti-inflammatory targets, and that GC treatment of quiescent macrophages globally directs GRIP1 toward GR binding sites dominated by palindromic GC response elements (GRE), suggesting a non-redundant GRIP1 function as a GR coactivator. Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. Consistently, phospho-GRIP1 and CDK9 are not detected at GR transrepression sites near pro-inflammatory genes. Thus, GR restricts actions of its own coregulator via CDK9-mediated phosphorylation to a subset of anti-inflammatory genes.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Adaptor Proteins, Signal Transducing / deficiency
-
Adaptor Proteins, Signal Transducing / genetics
-
Adaptor Proteins, Signal Transducing / metabolism*
-
Animals
-
Binding Sites / genetics
-
Carrier Proteins / antagonists & inhibitors
-
Carrier Proteins / genetics
-
Carrier Proteins / metabolism*
-
Cell Line
-
Cells, Cultured
-
Cyclin-Dependent Kinase 9 / metabolism*
-
Dexamethasone / pharmacology
-
Gene Knockdown Techniques
-
Glucocorticoids / metabolism*
-
Glucocorticoids / pharmacology
-
Humans
-
Inflammation / genetics
-
Inflammation / metabolism
-
Macrophages / drug effects
-
Macrophages / metabolism*
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Models, Biological
-
Nerve Tissue Proteins / antagonists & inhibitors
-
Nerve Tissue Proteins / deficiency
-
Nerve Tissue Proteins / genetics
-
Nerve Tissue Proteins / metabolism*
-
Phosphorylation
-
Receptors, Glucocorticoid / metabolism
-
Response Elements
-
Transcriptional Activation
Substances
-
Adaptor Proteins, Signal Transducing
-
Carrier Proteins
-
GRIP1 protein, human
-
Glucocorticoids
-
Grip1 protein, mouse
-
Nerve Tissue Proteins
-
Receptors, Glucocorticoid
-
Dexamethasone
-
CDK9 protein, human
-
Cdk9 protein, mouse
-
Cyclin-Dependent Kinase 9