PMID- 25825525 OWN - NLM STAT- MEDLINE DCOM- 20150707 LR - 20181113 IS - 1098-5549 (Electronic) IS - 0270-7306 (Print) IS - 0270-7306 (Linking) VI - 35 IP - 11 DP - 2015 Jun 1 TI - Modulation of Macrophage Gene Expression via Liver X Receptor alpha Serine 198 Phosphorylation. PG - 2024-34 LID - 10.1128/MCB.00985-14 [doi] AB - 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 LXRalpha 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 LXRalpha at S198 is nonphosphorylated. In bone marrow-derived macrophages (BMDMs), we also observed induction of CCR7 by ligands that promote nonphosphorylated LXRalpha S198, and this was lost in LXR-deficient BMDMs. LXRalpha occupancy at the CCR7 promoter is enhanced and histone modifications associated with gene repression are reduced in RAW264.7 cells expressing nonphosphorylated LXRalpha (RAW-LXRalpha S198A) compared to RAW264.7 cells expressing wild-type (WT) phosphorylated LXRalpha (RAW-LXRalpha WT). Expression profiling of ligand-treated RAW-LXRalpha S198A cells compared to RAW-LXRalpha WT cells revealed induction of cell migratory and anti-inflammatory genes and repression of proinflammatory genes. Modeling of LXRalpha 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 LXRalpha S198 phosphorylation, including that of antiatherogenic genes such as CCR7. CI - Copyright (c) 2015, American Society for Microbiology. All Rights Reserved. FAU - Wu, Chaowei AU - Wu C AD - Department of Microbiology, New York University School of Medicine, New York, New York, USA. FAU - Hussein, Maryem A AU - Hussein MA AD - Department of Microbiology, New York University School of Medicine, New York, New York, USA. FAU - Shrestha, Elina AU - Shrestha E AD - Department of Microbiology, New York University School of Medicine, New York, New York, USA. FAU - Leone, Sarah AU - Leone S AD - Department of Microbiology, New York University School of Medicine, New York, New York, USA. FAU - Aiyegbo, Mohammed S AU - Aiyegbo MS AD - Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA. FAU - Lambert, W Marcus AU - Lambert WM AD - Department of Microbiology, New York University School of Medicine, New York, New York, USA. FAU - Pourcet, Benoit AU - Pourcet B AD - Centre for Clinical Pharmacology, Division of Medicine, University College London, London, United Kingdom. FAU - Cardozo, Timothy AU - Cardozo T AD - Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA. FAU - Gustafson, Jan-Ake AU - Gustafson JA AD - Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA. FAU - Fisher, Edward A AU - Fisher EA AD - Department of Medicine, Division of Cardiology, Mark and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York, USA. FAU - Pineda-Torra, Ines AU - Pineda-Torra I AD - Centre for Clinical Pharmacology, Division of Medicine, University College London, London, United Kingdom i.torra@ucl.ac.uk michael.garabedian@nyumc.org. FAU - Garabedian, Michael J AU - Garabedian MJ AD - Department of Microbiology, New York University School of Medicine, New York, New York, USA i.torra@ucl.ac.uk michael.garabedian@nyumc.org. LA - eng SI - PDB/4NQA GR - R01 HL117226/HL/NHLBI NIH HHS/United States GR - 4DP2OD004631/OD/NIH HHS/United States GR - P30 CA016087/CA/NCI NIH HHS/United States GR - P01 HL098055/HL/NHLBI NIH HHS/United States GR - T32 GM007238/GM/NIGMS NIH HHS/United States GR - T32 AI007180/AI/NIAID NIH HHS/United States GR - T32GM007238/GM/NIGMS NIH HHS/United States GR - DP2 OD004631/OD/NIH HHS/United States GR - T32AI07180/AI/NIAID NIH HHS/United States GR - HL117226/HL/NHLBI NIH HHS/United States GR - G0801278/Medical Research Council/United Kingdom GR - R01 HL084312/HL/NHLBI NIH HHS/United States GR - HL084312/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150330 PL - United States TA - Mol Cell Biol JT - Molecular and cellular biology JID - 8109087 RN - 0 (Ligands) RN - 0 (Liver X Receptors) RN - 0 (NR1H3 protein, human) RN - 0 (Nr1h3 protein, mouse) RN - 0 (Orphan Nuclear Receptors) RN - 0 (Receptors, CCR7) RN - 452VLY9402 (Serine) SB - IM MH - Animals MH - Atherosclerosis/genetics MH - Cell Line MH - Gene Expression/*genetics MH - Humans MH - Ligands MH - Liver X Receptors MH - Macrophages/*metabolism MH - Mice MH - Mice, Inbred C57BL MH - Orphan Nuclear Receptors/*genetics MH - Phosphorylation/*genetics MH - Receptors, CCR7 MH - Serine/*genetics PMC - PMC4420924 EDAT- 2015/04/01 06:00 MHDA- 2015/07/08 06:00 PMCR- 2015/12/01 CRDT- 2015/04/01 06:00 PHST- 2014/07/29 00:00 [received] PHST- 2015/03/19 00:00 [accepted] PHST- 2015/04/01 06:00 [entrez] PHST- 2015/04/01 06:00 [pubmed] PHST- 2015/07/08 06:00 [medline] PHST- 2015/12/01 00:00 [pmc-release] AID - MCB.00985-14 [pii] AID - 00985-14 [pii] AID - 10.1128/MCB.00985-14 [doi] PST - ppublish SO - Mol Cell Biol. 2015 Jun 1;35(11):2024-34. doi: 10.1128/MCB.00985-14. Epub 2015 Mar 30.