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Molecular and Cellular Biology, April 2008, p. 2626-2636, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.01575-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Inés Pineda Torra,¹ Naima Ismaili,¹ Jonathan E. Feig,² Chong-Feng Xu,⁴ Claudio Cavasotto,^3, Raluca Pancratov,⁴ Inez Rogatsky,⁵ Thomas A. Neubert,⁴ Edward A. Fisher,² and Michael J. Garabedian^1*

Departments of Microbiology and Urology,¹ Medicine and Cell Biology,² Pharmacology and the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016,⁴ MolSoft LLC, La Jolla, California 92037,³ Hospital for Special Surgery, Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021⁵

Received 27 August 2007/ Returned for modification 26 September 2007/ Accepted 28 January 2008

Dysregulation of liver X receptor (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 RAW 264.7 cells expressing the LXR 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 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.

Published ahead of print on 4 February 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: School of Health Information Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030.

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