Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-01569-2
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Funding
- NIH NIAMS [T32 AR007281]
- NIH [3R01DK099087-01A1S1, R01DK099087, R01GM104291]
- MSTP from the NIH NIGMS [T32GM007739]
- Rheumatology Research Foundation
- DOD [CDMRP PR130049]
- Hospital for Special Surgery David Rosensweig Genomics Center
- Ministry of Science and Technology of China National Key Research Project [2015CB943201]
- National Natural Science Foundation [81422019, 81571580, 91642115, 8151101184]
- Tsinghua-Peking Center for Life Sciences
- V Foundation
- Roy J. Carver Charitable Trust [01-224]
- [K99/R00 CA149088]
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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.
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