Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways.
Innate immune responses to bacterial or viral infection require rapid transition of large cohorts of inflammatory response genes from poised/repressed to actively transcribed states, but the underlying repression/derepression mechanisms remain poorly understood. Here, we report that, while the nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressors establish repression checkpoints on broad sets of inflammatory response genes in macrophages and are required for nearly all of the transrepression activities of liver X receptors (LXRs), they can be selectively recruited via c-Jun or the Ets repressor Tel, respectively, establishing NCoR-specific, SMRT-specific, and NCoR/SMRT-dependent promoters. Unexpectedly, the binding of NCoR and SMRT to NCoR/SMRT-dependent promoters is frequently mutually dependent, establishing a requirement for both proteins for LXR transrepression and enabling inflammatory signaling pathways that selectively target NCoR or SMRT to also derepress/activate NCoR/SMRT-dependent genes. These findings reveal a combinatorial, corepressor-based strategy for integration of inflammatory and anti-inflammatory signals that play essential roles in immunity and homeostasis.
Ghisletti
Serena
S
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.
Huang
Wendy
W
Jepsen
Kristen
K
Benner
Chris
C
Hardiman
Gary
G
Rosenfeld
Michael G
MG
Glass
Christopher K
CK
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000276:immunology; D000071518:Liver X Receptors; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D057093:Orphan Nuclear Receptors; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C539128:Ncor1 protein, mouse; C539131:Ncor2 protein, mouse; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D048031:JNK Mitogen-Activated Protein Kinases