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

• Published in: Nature communications Vol. 8; no. 1; pp. 1739 - 15
• Main Authors: Rollins, David A., Kharlyngdoh, Joubert B., Coppo, Maddalena, Tharmalingam, Bowranigan, Mimouna, Sanda, Guo, Ziyi, Sacta, Maria A., Pufall, Miles A., Fisher, Robert P., Hu, Xiaoyu, Chinenov, Yurii, Rogatsky, Inez
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.11.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/2504/342; 631/250/251/1574; 631/250/256; 631/337/572; Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Binding sites; Binding Sites - genetics; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Cells, Cultured; Cyclin-dependent kinase; Cyclin-Dependent Kinase 9 - metabolism; Cyclin-dependent kinases; Dexamethasone - pharmacology; Gene Knockdown Techniques; Genes; Glucocorticoids; Glucocorticoids - metabolism; Glucocorticoids - pharmacology; GRIP1 protein; Humanities and Social Sciences; Humans; Inflammation; Inflammation - genetics; Inflammation - metabolism; Isoforms; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; multidisciplinary; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Phosphorylation; Receptors, Glucocorticoid - metabolism; Regulatory sequences; Response Elements; Science; Science (multidisciplinary); Transcription; Transcriptional Activation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01569-2

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. Glucocorticoid reduces inflammation by both inducing anti-inflammatory genes and suppressing pro-inflammatory genes, but how these two functions are dictated is unclear. Here the authors show that phosphorylated glucocorticoid receptor-interacting protein 1 (GRIP1) serves as a coactivator for this response in macrophage.