Phosphorylation of liver X receptor alpha selectively regulates target gene expression in macrophages.
Dysregulation of liver X receptor alpha (LXRalpha) activity has been linked to cardiovascular and metabolic diseases. Here, we show that LXRalpha target gene selectivity is achieved by modulation of LXRalpha phosphorylation. Under basal conditions, LXRalpha is phosphorylated at S198; phosphorylation is enhanced by LXR ligands and reduced both by casein kinase 2 (CK2) inhibitors and by activation of its heterodimeric partner RXR with 9-cis-retinoic acid (9cRA). Expression of some (AIM and LPL), but not other (ABCA1 or SREBPc1) established LXR target genes is increased in RAW 264.7 cells expressing the LXRalpha S198A phosphorylation-deficient mutant compared to those with WT receptors. Surprisingly, a gene normally not expressed in macrophages, the chemokine CCL24, is activated specifically in cells expressing LXRalpha S198A. Furthermore, inhibition of S198 phosphorylation by 9cRA or by a CK2 inhibitor similarly promotes CCL24 expression, thereby phenocopying the S198A mutation. Thus, our findings reveal a previously unrecognized role for phosphorylation in restricting the repertoire of LXRalpha-responsive genes.
Torra
Inés Pineda
IP
Department of Microbiology, NYU School of Medicine, New York, NY 10016, USA.
Ismaili
Naima
N
Feig
Jonathan E
JE
Xu
Chong-Feng
CF
Cavasotto
Claudio
C
Pancratov
Raluca
R
Rogatsky
Inez
I
Neubert
Thomas A
TA
Fisher
Edward A
EA
Garabedian
Michael J
MJ
D000595:Amino Acid Sequence; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D047390:Casein Kinase II / Q000378:metabolism; D002460:Cell Line; D054423:Chemokine CCL24 / Q000378:metabolism; D002784:Cholesterol / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D057093:Orphan Nuclear Receptors; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
D054423:Chemokine CCL24; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors; D010768:Phosphoserine; D002784:Cholesterol; D047390:Casein Kinase II