The GRIP1:IRF3 interaction as a target for glucocorticoid receptor-mediated immunosuppression.
Glucocorticoids dramatically inhibit cytokine and chemokine production. They act through the glucocorticoid receptor (GR), a ligand-dependent transcription factor that binds to and represses activities of other DNA-bound regulators, activator protein 1 and nuclear factor kappaB, utilizing a p160 GRIP1 as a corepressor. A yeast two-hybrid screen with the GRIP1 corepression domain (RD) yielded interferon (IFN) regulatory factor (IRF)3-a downstream effector of Toll-like receptors (TLR) 3/4 and an essential activator of several IFN and chemokine genes. We defined the GRIP1:IRF3 interface and showed that endogenous GRIP1 and IRF3 interact in mammalian cells. Interestingly, GR and IRF3 competed for GRIP1 binding; GR activation or GRIP1 knockdown in macrophages blocked whereas GRIP1 overexpression rescued IRF3-dependent gene expression. GR interference persisted in MyD88- and IFNA receptor-deficient mice, suggesting a specific disruption of TLR3-IRF3 pathway, not of autocrine IFN signaling. Finally, IRF3-stimulated response elements were necessary and sufficient for TLR3-dependent induction and glucocorticoid inhibition. Thus, GRIP1 plays a cofactor role in innate immunity. Competition with GR for GRIP1 antagonizes IRF3-mediated transcription, identifying the GRIP1:IRF3 interaction as a novel target for glucocorticoid immunosuppression.
Reily
Michael M
MM
Hospital for Special Surgery, Department of Microbiology & Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Pantoja
Carlos
C
Hu
Xiaoyu
X
Chinenov
Yurii
Y
Rogatsky
Inez
I
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D007165:Immunosuppression Therapy; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D017471:Receptors, Interferon / Q000235:genetics; D020218:Response Elements / Q000187:drug effects; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D005938:Glucocorticoids; D050838:Interferon Regulatory Factor-3; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051958:Nuclear Receptor Coactivator 2; D011965:Receptors, Glucocorticoid; D017471:Receptors, Interferon; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta