Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, 1300 York Avenue, New York, NY, 10021, USA.
Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, 10021, USA.
Nat Commun. 2017 Nov 23;8(1):1739. 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.
糖皮质激素（GC）受体（GR）通过激活抗炎基因和抑制促炎基因来抑制炎症。GR 相互作用蛋白 1（GRIP1）是巨噬细胞中的 GR 核心抑制剂，但 GRIP1 是否介导 GR 激活的转录，以及决定其共激活剂与核心抑制剂特性的因素尚不清楚。在这里，我们报告巨噬细胞中 GRIP1 的缺失会减弱糖皮质激素诱导的几种抗炎靶基因的表达，而静止巨噬细胞中 GC 的处理会将 GRIP1 全局导向由回文糖皮质激素反应元件（GRE）主导的 GR 结合位点，这表明 GRIP1 作为 GR 共激活剂具有非冗余功能。有趣的是，GRIP1 的 N 端丝氨酸簇被周期蛋白依赖性激酶-9（CDK9）磷酸化，CDK9 被募集到 GC 诱导的 GR:GRIP1:CDK9 异源复合物中，产生独特的 GRE 特异性 GRIP1 磷酸化异构体。磷酸化增强了 GRIP1 的共激活剂作用，但令人惊讶的是，它的核心抑制剂特性没有增强。一致地，GR 转录阻遏位点附近的促炎基因附近没有检测到磷酸化的 GRIP1 和 CDK9。因此，GR 通过 CDK9 介导的磷酸化将其自身共调节剂的作用限制在一组抗炎基因上。
