Ghisletti Serena, Huang Wendy, Ogawa Sumito, Pascual Gabriel, Lin Mu-En, Willson Timothy M, Rosenfeld Michael G, Glass Christopher K
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Mol Cell. 2007 Jan 12;25(1):57-70. doi: 10.1016/j.molcel.2006.11.022.
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.
转录抑制被广泛用于负向调节基因表达，但不同核受体实现基因和信号特异性转录抑制程序的机制仍知之甚少。在此，我们报告了替代性的依赖小泛素样修饰物（SUMO）的机制的鉴定，这些机制使过氧化物酶体增殖物激活受体γ（PPARγ）和肝X受体（LXRs）能够负向调节促炎基因的重叠但不同的子集。SUMO2/3与LXRs的配体依赖性缀合或SUMO1与PPARγ的配体依赖性缀合将它们靶向Toll样受体（TLR）靶基因的启动子，在那里它们阻止转录激活所需的核受体辅阻遏物（NCoR）复合物的信号依赖性去除。SUMO1-PPARγ和SUMO2/3-LXRs抑制不同的NCoR清除机制，从而实现启动子和TLR特异性的抑制模式。突变分析和对天然存在的氧化甾醇配体的研究表明，LXRs的反式激活和依赖SUMO化的转录抑制活性可以独立调节。这些研究定义了PPARγ和LXRs利用的平行但功能不同的途径，以差异调节控制免疫和体内平衡的复杂基因表达程序。
