Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARγ
Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARγ
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DOI：
10.1016/j.molcel.2006.11.022
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发表时间：
2007-01-12
期刊：
影响因子：
16
通讯作者：
Glass, Christopher K.
中科院分区：
文献类型：
--
作者：
Ghisletti, Serena;Huang, Wendy;Glass, Christopher K.
反式阻遏被广泛用于负调控基因表达，但不同的核受体影响基因和信号特异性反式阻遏程序的机制仍然知之甚少。在这里，我们报告的替代SUMO化依赖的机制，使PPARgamma和LXRs负调控重叠，但不同的子集的促炎基因的鉴定。SUMO 2/3与LXR或SUMO 1与PPAR γ的配体依赖性缀合将它们靶向TLR靶基因的启动子，在那里它们阻止转录激活所需的NCoR辅阻遏物复合物的信号依赖性去除。SUMO 1-PPAR γ和SUMO 2/3LXR抑制不同的NCoR清除机制，允许启动子和TLR特异性抑制模式。突变分析和天然存在的氧固醇配体的研究表明，LXR的反式激活和SUMO化依赖的反式阻遏活性可以独立调节。这些研究定义了并行但功能不同的途径，这些途径被PPAR γ和LXR用于差异调节控制免疫和稳态的基因表达的复杂程序。
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 PPAR gamma and LXRs to negatively regulate overlapping but distinct subsets of proinflammatory genes. Ligand-dependent conjugation of SUMO2/3 to LXRs or SUMO1 to PPAR gamma targets them to promoters of TLR target genes, where they prevent the signal-dependent removal of NCoR corepressor complexes required for transcriptional activation. SUMO1-PPAR gamma and SUMO2/3LXRs 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 PPAR gamma and LXRs to differentially regulate complex programs of gene expression that control immunity and homeostasis.