Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 35, Issue 11, Pages 2024-2034Publisher
TAYLOR & FRANCIS INC
DOI: 10.1128/MCB.00985-14
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Funding
- NIH [HL084312, P01 HL098055, HL117226, 4DP2OD004631]
- NIH training grant [T32GM007238, T32AI07180]
- Medical Research Council New Investigator grant [G0801278]
- MRC [G0801278] Funding Source: UKRI
- Medical Research Council [G0801278] Funding Source: researchfish
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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 LXR alpha 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 LXR alpha at S198 is nonphosphorylated. In bone marrow-derived macrophages (BMDMs), we also observed induction of CCR7 by ligands that promote nonphosphorylated LXR alpha S198, and this was lost in LXR-deficient BMDMs. LXR alpha occupancy at the CCR7 promoter is enhanced and histone modifications associated with gene repression are reduced in RAW264.7 cells expressing nonphosphorylated LXR alpha (RAW-LXR alpha S198A) compared to RAW264.7 cells expressing wild-type (WT) phosphorylated LXR alpha (RAW-LXR alpha WT). Expression profiling of ligand-treated RAW-LXR alpha S198A cells compared to RAW-LXR alpha WT cells revealed induction of cell migratory and anti-inflammatory genes and repression of proinflammatory genes. Modeling of LXR alpha 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 LXR alpha S198 phosphorylation, including that of antiatherogenic genes such as CCR7.
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