Glucocorticoid-induced phosphorylation by CDK9 modulates the coactivator functions of transcriptional cofactor GRIP1 in macrophages

David A. Rollins, Joubert B. Kharlyngdoh, Maddalena Coppo, Bowranigan Tharmalingam, Sanda Mimouna, Ziyi Guo, Maria A. Sacta, Miles A. Pufall, Robert P. Fisher, Xiaoyu Hu, Yurii Chinenov and Inez Rogatsky ()
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David A. Rollins: Weill Cornell Graduate School of Medical Sciences
Joubert B. Kharlyngdoh: The David Rosensweig Genomics Center
Maddalena Coppo: The David Rosensweig Genomics Center
Bowranigan Tharmalingam: The David Rosensweig Genomics Center
Sanda Mimouna: The David Rosensweig Genomics Center
Ziyi Guo: Tsinghua University
Maria A. Sacta: The David Rosensweig Genomics Center
Miles A. Pufall: University of Iowa
Robert P. Fisher: Icahn School of Medicine at Mount Sinai
Xiaoyu Hu: The David Rosensweig Genomics Center
Yurii Chinenov: The David Rosensweig Genomics Center
Inez Rogatsky: Weill Cornell Graduate School of Medical Sciences

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01569-2

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