The GRIP1:IRF3 interaction as a target for glucocorticoid receptor-mediated immunosuppression

Authors:
Reily MM, Pantoja C, Hu X, Chinenov Y and Rogatsky I
In:
Source: EMBO J
Publication Date: (2006)
Issue: 25(1): 108-117
Research Area:
Immunotherapy / Hematology
Cells used in publication:
RAW 264.7
Species: mouse
Tissue Origin: blood
Platform:
Nucleofectorâ„¢ I/II/2b
Abstract
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.