Institute of Molecular Biology and Tumor Research-IMT, Philipps University, Marburg, Germany.
PLoS One. 2013 Apr 30;8(4):e63011. doi: 10.1371/journal.pone.0063011. Print 2013.
The peroxisome proliferator-activated receptor subtypes PPARα, PPARβ/δ, PPARγ are members of the steroid hormone receptor superfamily with well-established functions in transcriptional regulation. Here, we describe an unexpected cytoplasmic function of PPARβ/δ. Silencing of PPARβ/δ expression interferes with the expression of a large subset of interleukin-1β (IL-1β)-induced target genes in HeLa cells, which is preceded by an inhibition of the IL-1β-induced phosphorylation of TAK1 and its downstream effectors, including the NFκBα inhibitor IκBα (NFKBIA) and the NFκBα subunit p65 (RELA). PPARβ/δ enhances the interaction between TAK1 and the small heat-shock protein HSP27, a known positive modulator of TAK1-mediated IL-1β signaling. Consistent with these findings, PPARβ/δ physically interacts with both the endogenous cytoplasmic TAK1/TAB1 complex and HSP27, and PPARβ/δ overexpression increases the TAK1-induced transcriptional activity of NFκB. These observations suggest that PPARβ/δ plays a role in the assembly of a cytoplasmic multi-protein complex containing TAK1, TAB1, HSP27 and PPARβ/δ, and thereby participates in the NFκB response to IL-1β.
过氧化物酶体增殖物激活受体亚型 PPARα、PPARβ/δ、PPARγ 是甾体激素受体超家族的成员，在转录调控中具有明确的功能。在这里，我们描述了 PPARβ/δ 的一个意想不到的细胞质功能。沉默 PPARβ/δ 的表达会干扰 HeLa 细胞中一大类白细胞介素-1β（IL-1β）诱导的靶基因的表达，这是 IL-1β 诱导的 TAK1 及其下游效应物（包括 NFκBα 抑制剂 IκBα（NFKBIA）和 NFκBα 亚基 p65（RELA））磷酸化的抑制所导致的。PPARβ/δ 增强了 TAK1 和小分子热休克蛋白 HSP27 之间的相互作用，HSP27 是 TAK1 介导的 IL-1β 信号的已知正调节剂。与这些发现一致，PPARβ/δ 与内源性细胞质 TAK1/TAB1 复合物和 HSP27 都发生物理相互作用，并且 PPARβ/δ 的过表达增加了 TAK1 诱导的 NFκB 的转录活性。这些观察结果表明，PPARβ/δ 在包含 TAK1、TAB1、HSP27 和 PPARβ/δ 的细胞质多蛋白复合物的组装中发挥作用，并因此参与了 NFκB 对 IL-1β 的反应。
