Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma.
Transrepression is widely utilized to negatively regulate gene expression, but the mechanisms by which different nuclear receptors effect gene- and signal-specific transrepression programs remain poorly understood. Here, we report the identification of alternative SUMOylation-dependent mechanisms that enable PPARgamma and LXRs to negatively regulate overlapping but distinct subsets of proinflammatory genes. Ligand-dependent conjugation of SUMO2/3 to LXRs or SUMO1 to PPARgamma targets them to promoters of TLR target genes, where they prevent the signal-dependent removal of NCoR corepressor complexes required for transcriptional activation. SUMO1-PPARgamma and SUMO2/3-LXRs inhibit distinct NCoR clearance mechanisms, allowing promoter- and TLR-specific patterns of repression. Mutational analysis and studies of naturally occurring oxysterol ligands indicate that the transactivation and SUMOylation-dependent transrepression activities of LXRs can be independently regulated. These studies define parallel but functionally distinct pathways that are utilized by PPARgamma and LXRs to differentially regulate complex programs of gene expression that control immunity and homeostasis.
Ghisletti
Serena
S
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Huang
Wendy
W
Ogawa
Sumito
S
Pascual
Gabriel
G
Lin
Mu-En
ME
Willson
Timothy M
TM
Rosenfeld
Michael G
MG
Glass
Christopher K
CK
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D044767:Ubiquitin-Protein Ligases; C400300:HDAC4 protein, human; D006655:Histone Deacetylases