Phosphorylation of LXR alpha Selectively Regulates Target Gene Expression in Macrophages

Departments of Microbiology, Urology, Medicine and Cell Biology, Pharmacology and the Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, NY 10016; MolSoft LLC, La Jolla, CA 92037; Hospital for Special Surgery, Department of Microbiology & Immunology, Weill Medical College of Cornell University, New York, NY 10021

^* To whom correspondence should be addressed. Email: garabm01{at}med.nyu.edu.

	Abstract

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