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J. Biol. Chem., Vol. 280, Issue 41, 34538-34547, October 14, 2005
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Phosphorylation of RelA/p65 on Serine 536 Defines an I
B
-independent NF-B Pathway*
From the Laboratory of Immunology, NIA, National Institutes of Health, Baltimore, Maryland 21224
The association of the NF-
B p65/p50 dimer with IB
plays a pivotal role in regulating its nuclear translocation and gene transcription. In addition, serine phosphorylation at various sites of the p65 subunit has been shown to be important in initiating transcription. Here we demonstrate that the regulation of nuclear translocation of p65 phosphorylated at serine 536 is not dependent on IB. Stimulation of either Jurkat or normal human T cells resulted in the nuclear translocation of phospho-p65 (Ser536). In addition, the phospho-p65 (Ser536) was not associated with either IB or p50, and the nuclear translocation of phospho-p65 (Ser536), but not total p65, was unaffected by the proteosome inhibitor MG-132, which blocks IB protein degradation and prevents p65/p50 dimer nuclear translocation. Accordingly, the co-expression of a dominant negative mutant of IB blocked the transcriptional activity mediated by wild type but not the dominant positive p65 mutant (S536D). Furthermore, the transfection of the S536D form of p65 led to the induction of interleukin-8 transcription following stimulation, whereas the S536A form, which cannot be phosphorylated at this site, did not. Together, the findings suggest that p65 phosphorylated on serine 536 is not associated with or regulated by IB, that it has a distinct set of target genes, and that it may represent a noncanonical NF-B pathway that is independent of IB regulation.
Received for publication, May 4, 2005 , and in revised form, August 11, 2005.
* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Laboratory of Immunology, National Institute on Aging, 5600 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-558-8096; Fax: 410-558-8284; E-mail: sasakic{at}grc.nia.nih.gov.
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