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Molecular and Cellular Biology, May 2006, p. 3864-3874, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3864-3874.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Protein Methyltransferase 2 Inhibits NF-{kappa}B Function and Promotes Apoptosis{dagger}

Lakshmanan Ganesh,1,{ddagger} Takanobu Yoshimoto,2,{ddagger},§ Narayani C. Moorthy,1,¶ Wataru Akahata,1 Manfred Boehm,2,3 Elizabeth G. Nabel,2 and Gary J. Nabel1*

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, 40 Convent Dr., Bethesda, Maryland 20892-3005,1 National Heart, Lung, and Blood Institute, National Institutes of Health, Building 31, Room 5A48, 31 Center Dr.,2 Hatfield Clinical Research Center, Building 10 CRC, Room 5E-3132, 10 Center Dr., Bethesda, Maryland 208923

Received 29 November 2005/ Returned for modification 18 December 2005/ Accepted 18 February 2006

The protein arginine methyltransferases (PRMTs) include a family of proteins with related putative methyltransferase domains that modify chromatin and regulate cellular transcription. Although some family members, PRMT1 and PRMT4, have been implicated in transcriptional modulation or intracellular signaling, the roles of other PRMTs in diverse cellular processes have not been fully established. Here, we report that PRMT2 inhibits NF-{kappa}B-dependent transcription and promotes apoptosis. PRMT2 exerted this effect by blocking nuclear export of I{kappa}B-{alpha} through a leptomycin-sensitive pathway, increasing nuclear I{kappa}B-{alpha} and decreasing NF-{kappa}B DNA binding. The highly conserved S-adenosylmethionine-binding domain of PRMT2 mediated this effect. PRMT2 also rendered cells susceptible to apoptosis by cytokines or cytotoxic drugs, likely due to its effects on NF-{kappa}B. Mouse embryo fibroblasts from PRMT2 genetic knockouts showed elevated NF-{kappa}B activity and decreased susceptibility to apoptosis compared to wild-type or complemented cells. Taken together, these data suggest that PRMT2 inhibits cell activation and promotes programmed cell death through this NF-{kappa}B-dependent mechanism.

* Corresponding author. Mailing address: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, 40 Convent Dr., Bethesda, MD 20892-3005. Phone: (301) 496-1852. Fax: (301) 480-0274. E-mail: gnabel{at}nih.gov.

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

{ddagger} These authors contributed equally to this work.

§ Present address: Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

Present address: 21 Murrays Gate Rd., Chennai 600018, India.

Molecular and Cellular Biology, May 2006, p. 3864-3874, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3864-3874.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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