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J. Biol. Chem., Vol. 281, Issue 27, 18684-18690, July 7, 2006

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NIK Is Involved in Nucleosomal Regulation by Enhancing Histone H3 Phosphorylation by IKK^*

Gye Young Park^¶, Xuerong Wang, Ningning Hu^¶, Tetyana V. Pedchenko^¶, Timothy S. Blackwell^¶, and John W. Christman^¶1

From the Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois, Chicago, Illinois 60612, the Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee 37203, and the ^¶Department of Veterans Affairs, Nashville, Tennessee 37203

The exact physiological role of NF-B-inducing kinase (NIK) in the NF-B activation pathway has not been defined, although it is an upstream kinase of IKK. Recent studies have indicated that IKK is a nucleosomal modifier of NF-B signaling. We hypothesized that NIK generates a proximal signal that contributes to IKK modification of nucleosomal structure through phosphorylation of histone H3 and enhancement of target gene expression. By using a chromatin immunoprecipitation assay, our data show that endogenous IKK is recruited to the promoter site of several NF-B-dependent genes in macrophages. Our data show that immunoreactive NIK is rapidly recruited to nuclear compartment in macrophages in response to treatment with endotoxin where it augments phosphorylation of histone H3 by inducing phosphorylation and kinase activity of IKK. A small interfering RNA knockdown of NIK markedly reduces phosphorylation of histone H3 in endotoxin treated macrophages. These data, together, demonstrate a novel role for NIK as a histone H3 modifier, through an accessory pathway from NIK to IKK, that could play an important role in the endotoxin response through modification of nucleosomal structure.

Received for publication, January 24, 2006 , and in revised form, May 3, 2006.

^* This work was supported by the Department of Veterans Affairs and National Institutes of Health Grants HL 075557 and HL 66196. 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: Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois at Chicago, 840 South Wood St. (M/C 719), Chicago, IL 60612. Tel.: 312-996-8039; Fax: 312-996-4665; E-mail: jwc{at}uic.edu.

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