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Molecular and Cellular Biology, September 2005, p. 7966-7975, Vol. 25, No. 18
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.18.7966-7975.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

NF-{kappa}B RelA Phosphorylation Regulates RelA Acetylation{dagger}

Lin-Feng Chen,1* Samuel A. Williams,1 Yajun Mu,1,{ddagger} Hiroyasu Nakano,4 James M. Duerr,5 Leonard Buckbinder,5 and Warner C. Greene1,2,3*

Gladstone Institute of Virology and Immunology,1 Departments of Medicine,2 Microbiology and Immunology, University of California, San Francisco, California 94141,3 Department of Immunology, Juntendo University, Tokyo, Japan,4 Pfizer Global R & D, Groton, Connecticut 063405

Received 5 April 2005/ Returned for modification 20 May 2005/ Accepted 15 June 2005

The nuclear functions of NF-{kappa}B p50/RelA heterodimers are regulated in part by posttranslational modifications of its RelA subunit, including phosphorylation and acetylation. Acetylation at lysines 218, 221, and 310 differentially regulates RelA's DNA binding activity, assembly with I{kappa}B{alpha}, and transcriptional activity. However, it remains unclear whether the acetylation is regulated or simply due to stimulus-coupled nuclear translocation of NF-{kappa}B. Using anti-acetylated lysine 310 RelA antibodies, we detected p300-mediated acetylation of RelA in vitro and in vivo after stimulation of cells with tumor necrosis factor alpha (TNF-{alpha}). Coexpression of catalytically inactive mutants of the catalytic subunit of protein kinase A/mitogen- and stress-activated kinase 1 or IKK1/IKK2, which phosphorylate RelA on serine 276 or serine 536, respectively, sharply inhibited RelA acetylation on lysine 310. Furthermore, phosphorylation of RelA on serine 276 or serine 536 increased assembly of phospho-RelA with p300, which enhanced acetylation on lysine 310. Reconstitution of RelA-deficient murine embryonic fibroblasts with RelA S276A or RelA S536A decreased TNF-{alpha}-induced acetylation of lysine 310 and expression of the endogenous NF-{kappa}B-responsive E-selectin gene. These findings indicate that the acetylation of RelA at lysine 310 is importantly regulated by prior phosphorylation of serines 276 and 536. Such phosphorylated and acetylated forms of RelA display enhanced transcriptional activity.

* Corresponding author. Mailing address: Gladstone Institute of Virology and Immunology, 1650 Owens St., San Francisco, CA 94158. Phone: (415) 734-4805. Fax: (415) 355-0153. E-mail for Lin-Feng Chen: lchen{at}gladstone.ucsf.edu. E-mail for Warner C. Greene: wgreene{at}gladstone.ucsf.edu.

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

{ddagger} Present address: Protein Design Labs, Inc., 34801 Campus Drive, Fremont, CA 94555.

Molecular and Cellular Biology, September 2005, p. 7966-7975, Vol. 25, No. 18
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.18.7966-7975.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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