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

Author

Listed:
  • David A. Rollins

    (Weill Cornell Graduate School of Medical Sciences
    The David Rosensweig Genomics Center)

  • 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
    Weill Cornell/ Sloan Kettering/ Rockefeller Tri-Institutional MD-PhD Program)

  • Miles A. Pufall

    (University of Iowa)

  • Robert P. Fisher

    (Icahn School of Medicine at Mount Sinai)

  • Xiaoyu Hu

    (The David Rosensweig Genomics Center
    Tsinghua University)

  • Yurii Chinenov

    (The David Rosensweig Genomics Center)

  • Inez Rogatsky

    (Weill Cornell Graduate School of Medical Sciences
    The David Rosensweig Genomics Center)

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.

Suggested Citation

  • 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 & In, 2017. "Glucocorticoid-induced phosphorylation by CDK9 modulates the coactivator functions of transcriptional cofactor GRIP1 in macrophages," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01569-2
    DOI: 10.1038/s41467-017-01569-2
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    Cited by:

    1. Dinesh K. Deochand & Marija Dacic & Michael J. Bale & Andrew W. Daman & Vidyanath Chaudhary & Steven Z. Josefowicz & David Oliver & Yurii Chinenov & Inez Rogatsky, 2024. "Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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