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J. Biol. Chem. 277 (47): 44623-44630

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Lipopolysaccharide-induced Methylation of HuR, an mRNA-stabilizing Protein, by CARM1*

Hongwei LiDagger , Sungmin Park§, Britta Kilburn||, Mary Anne Jelinek||, Agnes Henschen-Edman**, Dana W. Aswad**, Michael R. StallcupDagger §Dagger Dagger , and Ite A. Laird-Offringa§Dagger Dagger §§

From the Departments of Dagger  Pathology and § Biochemistry and Molecular Biology,  Norris Cancer Center, University of Southern California, Keck School of Medicine, Los Angeles, California 90089-9176, || Upstate Biotechnology, Inc., Lake Placid, New York 12946, and the ** Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900

The RNA-binding protein HuR stabilizes labile mRNAs carrying AU-rich instability elements. This mRNA stabilization can be induced by hypoxia, lipopolysaccharide, and UV light. The mechanism by which these stimuli activate HuR is unclear and might be related to post-translational modification of this protein. Here we show that HuR can be methylated on arginine. However, HuR is not a substrate for PRMT1, the most prominent protein-arginine methyltransferase in mammalian cells, which methylates a number of heterogeneous nuclear ribonucleoproteins. Instead, HuR is specifically methylated by coactivator-associated arginine methyltransferase 1 (CARM1), a protein-arginine methyltransferase previously shown to serve as a transcriptional coactivator. By analyzing methylation of specific HuR arginine-to-lysine mutants and by sequencing radioactively methylated HuR peptides, Arg217 was identified as the major HuR methylation site. Arg217 is located in the hinge region between the second and third of the three HuR RNA recognition motif domains. Antibodies against a methylated HuR peptide were used to demonstrate in vivo methylation of HuR. HuR methylation increased in cells that overexpressed CARM1. Importantly, lipopolysaccharide stimulation of macrophages, which leads to HuR-mediated stabilization of tumor necrosis factor alpha  mRNA in these cells, caused increased methylation of endogenous HuR. Thus, CARM1, which plays a role in transcriptional activation through histone H3 methylation, may also play a role in post-transcriptional gene regulation by methylating HuR.

* This work was supported by United States Public Health Service Grants DK55274 (to M. R. S.) and NS17269 (to D. W. A.) from the National Institutes of Health and by American Cancer Society Institutional Research Grant IRG-21-37, a grant from the American Lung Association, and National Institutes of Health Grant R29CA78407 (to I. A. L-O.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Dagger These authors contributed equally to this work.

§§ To whom correspondence should be addressed: Norris Cancer Center, University of Southern California, Keck School of Medicine, Los Angeles, CA 90089-9176. Tel.: 323-865-0655; Fax: 323-865-0158; E-mail: ilaird@usc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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