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J. Biol. Chem., Vol. 280, Issue 25, 23496-23501, June 24, 2005

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Bruton's Tyrosine Kinase Is Involved in p65-mediated Transactivation and Phosphorylation of p65 on Serine 536 during NFB Activation by Lipopolysaccharide^*

Sarah L. Doyle, Caroline A. Jefferies, and Luke A. O'Neill

From the Department of Biochemistry and Biotechnology Institute, Trinity College, Dublin 2, Ireland

Bruton's tyrosine kinase (Btk) has recently been shown to participate in the induction of nuclear factor B (NFB)-dependent gene expression by the lipopolysaccharide (LPS) receptor Toll-like receptor-4 (TLR4). In this study we have examined the mechanism whereby Btk participates in this response. Treatment of the murine monocytic cell line Raw264.7 with LFM-A13, a specific Btk inhibitor, blocked LPS-induced NFB-dependent reporter gene expression but not IB degradation. Transient transfection of HEK293 cells with Btk had no effect on NFB-dependent reporter gene expression but strongly promoted transactivation of a reporter gene by a p65-Gal4 fusion protein. IB degradation activated by LPS was intact in macrophages from X-linked immunodeficiency (Xid) mice, which contain inactive Btk. Transfection of cells with a dominant negative form of Btk (BtkK430R) inhibited LPS-driven p65 mediated transactivation. Additionally LFM-A13 impaired phosphorylation of serine 536 on p65 induced by LPS in HEK293-TLR4 cells, and in Xid macrophages this response was impaired. This study therefore reveals a novel function for Btk. It is required for the signaling pathway activated by TLR4, which culminates in phosphorylation of p65 on serine 536 promoting transactivation by NFB.

Received for publication, February 8, 2005 , and in revised form, April 15, 2005.

^* This work was supported by Science Foundation Ireland. 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.

These authors contributed equally to this study.

To whom correspondence should be addressed. Tel.: 353-1-608-2439; Fax: 353-1-677-2400; E-mail: laoneill{at}tcd.ie.

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