Modulation of Macrophage Gene Expression via Liver X Receptor α Serine 198 Phosphorylation.
Modulation of Macrophage Gene Expression via Liver X Receptor α Serine 198 Phosphorylation.
复制标题
通过肝脏 X 受体α丝氨酸 198 磷酸化调节巨噬细胞基因表达。
DOI：
10.1128/mcb.00985-14
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发表时间：
2015
影响因子：
5.3
通讯作者：
Garabedian,MichaelJ
中科院分区：
文献类型：
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作者：
Wu,Chaowei;Hussein,MaryemA;Shrestha,Elina;Leone,Sarah;Aiyegbo,MohammedS;Lambert,WMarcus;Pourcet,Benoit;Cardozo,Timothy;Gustafson,Jan-Ake;Fisher,EdwardA;Pineda-Torra,Ines;Garabedian,MichaelJ
在小鼠动脉粥样硬化模型中，高脂血症的正常化促进巨噬细胞迁移和动脉粥样硬化斑块的消退，部分是通过肝脏X受体（LXR）介导的趋化因子受体CCR 7的诱导。在这里，我们报告LXRα丝氨酸198（S198）磷酸化调节CCR 7的表达。在观察到高水平CCR 7表达的消退环境中，在斑块巨噬细胞中观察到低水平的S198磷酸化。与这些发现一致，当S198处的LXRα非磷酸化时，人和小鼠巨噬细胞系中的CCR 7基因表达被诱导。在骨髓源性巨噬细胞（BMDM）中，我们还观察到促进非磷酸化LXRα S198的配体对CCR 7的诱导，而这在LXR缺陷的BMDM中丢失。与表达野生型（WT）磷酸化LXR α（RAW-LXRα WT）的RAW264.7细胞相比，表达非磷酸化LXR α（RAW-LXRα S198 A）的RAW264.7细胞中CCR 7启动子处的LXRα占据率增强，与基因阻遏相关的组蛋白修饰减少。与RAW-LXRα WT细胞相比，配体处理的RAW-LXRα S198 A细胞的表达谱显示细胞迁移和抗炎基因的诱导以及促炎基因的抑制。在非磷酸化和磷酸化状态下对LXRα S198进行建模，发现铰链区的磷酸化依赖性构象变化与蛋白质相互作用位点的存在相称。因此，基因转录受LXRα S198磷酸化调节，包括抗动脉粥样硬化基因如CCR 7。
In mouse models of atherosclerosis, normalization of hyperlipidemia promotes macrophage emigration and regression of atherosclerotic plaques in part by liver X receptor (LXR)-mediated induction of the chemokine receptor CCR7. Here we report that LXRα serine 198 (S198) phosphorylation modulates CCR7 expression. Low levels of S198 phosphorylation are observed in plaque macrophages in the regression environment where high levels of CCR7 expression are observed. Consistent with these findings, CCR7 gene expression in human and mouse macrophages cell lines is induced when LXRα at S198 is nonphosphorylated. In bone marrow-derived macrophages (BMDMs), we also observed induction of CCR7 by ligands that promote nonphosphorylated LXRα S198, and this was lost in LXR-deficient BMDMs. LXRα occupancy at the CCR7 promoter is enhanced and histone modifications associated with gene repression are reduced in RAW264.7 cells expressing nonphosphorylated LXRα (RAW-LXRα S198A) compared to RAW264.7 cells expressing wild-type (WT) phosphorylated LXRα (RAW-LXRα WT). Expression profiling of ligand-treated RAW-LXRα S198A cells compared to RAW-LXRα WT cells revealed induction of cell migratory and anti-inflammatory genes and repression of proinflammatory genes. Modeling of LXRα S198 in the nonphosphorylated and phosphorylated states identified phosphorylation-dependent conformational changes in the hinge region commensurate with the presence of sites for protein interaction. Therefore, gene transcription is regulated by LXRα S198 phosphorylation, including that of antiatherogenic genes such as CCR7.