Phosphorylation of LXR alpha Selectively Regulates Target Gene Expression in Macrophages

Authors:
Torra IP, Ismaili N, Feig JE, Xu CF, Cavasotto C, Pancratov R, Rogatsky I, Neubert TA, Fisher EA, Garabedian MJ
In:
Source: Mol Cell Biol
Publication Date: (2008)
Issue: 28(8): 2626-36
Research Area:
Immunotherapy / Hematology
Cells used in publication:
RAW 264.7
Species: mouse
Tissue Origin: blood
Platform:
Nucleofectorâ„¢ I/II/2b
Abstract
Dysregulation of 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 RAW264.7 cells expressing the LXRalpha S198A phosphorylation-deficient mutant compared to those with wild-type receptor. 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.