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.

[1]  M. Rosenfeld,et al.  Cooperative regulation in development by SMRT and FOXP1. , 2008, Genes & development.

[2]  O. Hermanson,et al.  SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron , 2007, Nature.

[3]  R. Luna,et al.  Differential Repression of c-myc and cdc2 Gene Expression by ERF and PE-1/METS , 2007, Cell cycle.

[4]  A. Bowie,et al.  The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling , 2007, Nature Reviews Immunology.

[5]  Lai Wei,et al.  Identification of CXCL11 as a STAT3-Dependent Gene Induced by IFN1 , 2007, The Journal of Immunology.

[6]  T. Willson,et al.  Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. , 2007, Molecular cell.

[7]  W. Hsueh,et al.  A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor , 2006, Circulation research.

[8]  J. Gustafsson,et al.  Liver X Receptor (LXR)-β Regulation in LXRα-Deficient Mice: Implications for Therapeutic Targeting , 2006, Molecular Pharmacology.

[9]  K. Honda,et al.  IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors , 2006, Nature Reviews Immunology.

[10]  Michael Karin,et al.  NF-κB: linking inflammation and immunity to cancer development and progression , 2005, Nature Reviews Immunology.

[11]  Amir Gamliel,et al.  A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ , 2005, Nature.

[12]  A. Hoffmann,et al.  A c-Rel subdomain responsible for enhanced DNA-binding affinity and selective gene activation. , 2005, Genes & development.

[13]  A. Hoffmann,et al.  Molecular Determinants of Crosstalk between Nuclear Receptors and Toll-like Receptors , 2005, Cell.

[14]  P. de la Torre,et al.  Interleukin-6 increases rat metalloproteinase-13 gene expression through Janus kinase-2-mediated inhibition of serine/threonine phosphatase-2A. , 2005, Cellular signalling.

[15]  M. Privalsky,et al.  SMRT and N-CoR Corepressors Are Regulated by Distinct Kinase Signaling Pathways* , 2004, Journal of Biological Chemistry.

[16]  M. Mayo,et al.  SMRT derepression by the IkappaB kinase alpha: a prerequisite to NF-kappaB transcription and survival. , 2004, Molecular cell.

[17]  M. Mayo,et al.  SMRT Derepression by the IκB Kinase α , 2004 .

[18]  C. Glass,et al.  A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Shizuo Akira,et al.  Toll-like receptor signalling , 2004, Nature Reviews Immunology.

[20]  C. Glass,et al.  A Corepressor/Coactivator Exchange Complex Required for Transcriptional Activation by Nuclear Receptors and Other Regulated Transcription Factors , 2004, Cell.

[21]  S. Plevy,et al.  Activation of the Murine Interleukin-12 p40 Promoter by Functional Interactions between NFAT and ICSBP* , 2003, Journal of Biological Chemistry.

[22]  S. Smale,et al.  C/EBPβ Regulation in Lipopolysaccharide-Stimulated Macrophages , 2003, Molecular and Cellular Biology.

[23]  O. Hermanson,et al.  N-CoR controls differentiation of neural stem cells into astrocytes , 2002, Nature.

[24]  I. Verma,et al.  NF-κB regulation in the immune system , 2002, Nature Reviews Immunology.

[25]  Christopher K. Glass,et al.  Exchange of N-CoR Corepressor and Tip60 Coactivator Complexes Links Gene Expression by NF-κB and β-Amyloid Precursor Protein , 2002, Cell.

[26]  S. Roy,et al.  MEKK1 plays a critical role in activating the transcription factor C/EBP-β-dependent gene expression in response to IFN-γ , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[27]  C. Glass,et al.  An Induced Ets Repressor Complex Regulates Growth Arrest during Terminal Macrophage Differentiation , 2002, Cell.

[28]  Brian T Chait,et al.  The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. , 2002, Molecular cell.

[29]  S. Hiebert,et al.  TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3 , 2001, Oncogene.

[30]  K. Ozato,et al.  Coactivator p300 Acetylates the Interferon Regulatory Factor-2 in U937 Cells following Phorbol Ester Treatment* , 2001, The Journal of Biological Chemistry.

[31]  J. Ghysdael,et al.  Proteins of the ETS family with transcriptional repressor activity , 2000, Oncogene.

[32]  A. Hoffmann,et al.  Selective requirement for c-Rel during IL-12 P40 gene induction in macrophages. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[33]  M. Greaves,et al.  Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL-AML1 oncoprotein. , 2000, Blood.

[34]  Kristen Jepsen,et al.  Combinatorial Roles of the Nuclear Receptor Corepressor in Transcription and Development , 2000, Cell.

[35]  M. Privalsky,et al.  The SMRT Corepressor Is Regulated by a MEK-1 Kinase Pathway: Inhibition of Corepressor Function Is Associated with SMRT Phosphorylation and Nuclear Export , 2000, Molecular and Cellular Biology.

[36]  G. Trinchieri,et al.  An IFN-γ-Inducible Transcription Factor, IFN Consensus Sequence Binding Protein (ICSBP), Stimulates IL-12 p40 Expression in Macrophages , 2000, The Journal of Immunology.

[37]  R. Shiekhattar,et al.  A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness. , 2000, Genes & Development.

[38]  J. Cheong,et al.  Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptors, as a Novel Transcriptional Corepressor Molecule of Activating Protein-1, Nuclear Factor-κB, and Serum Response Factor* , 2000, The Journal of Biological Chemistry.

[39]  G. Nucifora,et al.  The leukemia-associated gene TEL encodes a transcription repressor which associates with SMRT and mSin3A. , 1999, Biochemical and biophysical research communications.

[40]  D. Brenner,et al.  Interleukin-6 Increases Rat Metalloproteinase-13 Gene Expression through Stimulation of Activator Protein 1 Transcription Factor in Cultured Fibroblasts* , 1999, The Journal of Biological Chemistry.

[41]  C. Glass,et al.  ETO, a Target of t(8;21) in Acute Leukemia, Interacts with the N-CoR and mSin3 Corepressors , 1998, Molecular and Cellular Biology.

[42]  T. Hoshino,et al.  ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[43]  G. Trinchieri,et al.  Synergistic Regulation of the Human Interleukin-12 p40 Promoter by NFκB and Ets Transcription Factors in Epstein-Barr Virus-transformed B Cells and Macrophages* , 1998, The Journal of Biological Chemistry.

[44]  S. Smale,et al.  Multiple control elements mediate activation of the murine and human interleukin 12 p40 promoters: evidence of functional synergy between C/EBP and Rel proteins , 1997, Molecular and cellular biology.

[45]  J. Pelletier,et al.  Cloning, sequencing and characterization of the 5'-flanking region of the human collagenase-3 gene. , 1997, The Biochemical journal.

[46]  C. López-Otín,et al.  Structural analysis and promoter characterization of the human collagenase-3 gene (MMP13). , 1997, Genomics.

[47]  Thorsten Heinzel,et al.  Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor , 1995, Nature.

[48]  K. Murphy,et al.  Regulation of interleukin 12 p40 expression through an NF-kappa B half-site , 1995, Molecular and cellular biology.

[49]  R. Evans,et al.  A transcriptional co-repressor that interacts with nuclear hormone receptors , 1995, Nature.

[50]  M. Karin,et al.  Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor , 1987, Cell.

[51]  丸山 砂穂.  Identification of IFN regulatory factor-1 binding site in IL-12 p40 gene promoter , 2007 .

[52]  Christopher K. Glass,et al.  Combinatorial roles of nuclear receptors in inflammation and immunity , 2006, Nature Reviews Immunology.

[53]  Lai Wei,et al.  Identification of CXCL 11 as a STAT 3-Dependent Gene Induced by IFN 1 , 2006 .

[54]  Peter Tontonoz,et al.  Reciprocal regulation of inflammation and lipid metabolism by liver X receptors , 2003, Nature Medicine.