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Originally published In Press as doi:10.1074/jbc.C100103200 on March 14, 2001

J. Biol. Chem., Vol. 276, Issue 18, 14602-14606, May 4, 2001
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Effects of the NIK aly Mutation on NF-kappa B Activation by the Epstein-Barr Virus Latent Infection Membrane Protein, Lymphotoxin beta  Receptor, and CD40*

Micah A. Luftig, Ellen Cahir-McFarland, George MosialosDagger , and Elliott Kieff§

From the Departments of Microbiology and Molecular Genetics and Medicine, Program in Virology, Harvard Medical School, Boston, Massachusetts, 02115

Homozygosity for the aly point mutation in NF-kappa B-inducing kinase (NIK) results in alymphoplasia in mice, a phenotype similar to that of homozygosity for deletion of the lymphotoxin beta  receptor (LTbeta R). We now find that NF-kappa B activation by Epstein-Barr virus latent membrane protein 1 (LMP1) or by an LMP1 transmembrane domain chimera with the LTbeta R signaling domain in human embryonic kidney 293 cells is selectively inhibited by a wild type dominant negative NIK comprised of amino acids 624-947 (DN-NIK) and not by aly DN-NIK. In contrast, LMP1/CD40 is inhibited by both wild type (wt) and aly DN-NIK. LMP1, an LMP1 transmembrane domain chimera with the LTbeta R signaling domain, and LMP1/CD40 activate NF-kappa B in wt or aly murine embryo fibroblasts. Although wt and aly NIK do not differ in their in vitro binding to tumor necrosis factor receptor-associated factor 1, 2, 3, or 6 or in their in vivo association with tumor necrosis factor receptor-associated factor 2 and differ marginally in their very poor binding to Ikappa B kinase beta  (IKKbeta ), only wt NIK is able to bind to IKKalpha . These data are compatible with a model in which activation of NF-kappa B by LMP1 and LTbeta R is mediated by an interaction of NIK or a NIK-like kinase with IKKalpha that is abrogated by the aly mutation. On the other hand, CD40 mediates NF-kappa B activation through a kinase that interacts with a different component of the IKK complex.

* This work was supported by National Institutes of Health Grant CA47006.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Present address: Biomedical Sciences Research Center "Al Fleming", Institute of Immunology, 14-16 Al Fleming Str., Vari, 16672, Athens, Greece.

§ To whom correspondence should be addressed. Tel.: 617-525-4250; Fax: 617-525-4251; E-mail: ekieff@rics.bwh.harvard.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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