Phosphorylation of Liver X Receptor alpha Selectively Regulates Target Gene Expression in Macrophages

PINEDA TORRA, I.; ISMAILI, N.; FEIG, J.E.; XU, C.; CAVASOTTO, CLAUDIO N.; PANCRATOV, R.; ROGATSKY, I.; NEUBERT, T.A.; FISHER, E.A.; GARABEDIAN, MICHAEL J.

MOLECULAR AND CELLULAR BIOLOGY

AMER SOC MICROBIOLOGY

Año: 2008 vol. 28 p. 2626 - 2636

0270-7306

Dysregulation of liver X receptor {alpha} (LXR{alpha}) activity has been linked to cardiovascular and metabolic diseases. Here, we show that LXR{alpha} target gene selectivity is achieved by modulation of LXR{alpha} phosphorylation. Under basal conditions, LXR{alpha} 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 LXR{alpha} 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 LXR{alpha} 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 LXR{alpha}-responsive genes.