Journal article
Glucocorticoid-induced phosphorylation by CDK9 modulates the coactivator functions of transcriptional cofactor GRIP1 in macrophages
Nature communications, Vol.8(1), 1739
11/23/2017
DOI: 10.1038/s41467-017-01569-2
PMCID: PMC5700924
PMID: 29170386
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.
Details
- Title: Subtitle
- Glucocorticoid-induced phosphorylation by CDK9 modulates the coactivator functions of transcriptional cofactor GRIP1 in macrophages
- Creators
- David A Rollins - Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, 10021, USAJoubert B Kharlyngdoh - Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, 10021, USAMaddalena Coppo - Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, 10021, USABowranigan Tharmalingam - Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, 10021, USASanda Mimouna - Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, 10021, USAZiyi Guo - Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, ChinaMaria A Sacta - Weill Cornell/ Sloan Kettering/ Rockefeller Tri-Institutional MD-PhD Program, 1300 York Avenue, New York, NY, 10021, USAMiles A Pufall - Department of Biochemistry, University of Iowa, 51 Newton Road, Iowa City, IA, 52242, USARobert P Fisher - Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USAXiaoyu Hu - Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, ChinaYurii Chinenov - Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, 10021, USAInez Rogatsky - Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, 10021, USA. rogatskyi@hss.edu
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.8(1), 1739
- DOI
- 10.1038/s41467-017-01569-2
- PMID
- 29170386
- PMCID
- PMC5700924
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- England
- Language
- English
- Date published
- 11/23/2017
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984024407502771
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