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Molecular and Cellular Biology, October 1998, p. 5899-5907, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Molecular Determinants of NF-kappa B-Inducing Kinase Action

Xin Lin,1 Yajun Mu,1 Emmett T. Cunningham Jr.,1 Kenneth B. Marcu,2 Romas Geleziunas,1 and Warner C. Greene1,3,*

Gladstone Institute of Virology and Immunology1 and Departments of Medicine, Microbiology and Immunology, University of California,3 San Francisco, California 94141, and Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, New York 11794-52152

Received 16 March 1998/Returned for modification 6 May 1998/Accepted 17 July 1998

NF-kappa B corresponds to an inducible eukaryotic transcription factor complex that is negatively regulated in resting cells by its physical assembly with a family of cytoplasmic ankyrin-rich inhibitors termed Ikappa B. Stimulation of cells with various proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha ), induces nuclear NF-kappa B expression. TNF-alpha signaling involves the recruitment of at least three proteins (TRADD, RIP, and TRAF2) to the type 1 TNF-alpha receptor tail, leading to the sequential activation of the downstream NF-kappa B-inducing kinase (NIK) and Ikappa B-specific kinases (IKKalpha and IKKbeta ). When activated, IKKalpha and IKKbeta directly phosphorylate the two N-terminal regulatory serines within Ikappa Balpha , triggering ubiquitination and rapid degradation of this inhibitor in the 26S proteasome. This process liberates the NF-kappa B complex, allowing it to translocate to the nucleus. In studies of NIK, we found that Thr-559 located within the activation loop of its kinase domain regulates NIK action. Alanine substitution of Thr-559 but not other serine or threonine residues within the activation loop abolishes its activity and its ability to phosphorylate and activate IKKalpha . Such a NIK-T559A mutant also dominantly interferes with TNF-alpha induction of NF-kappa B. We also found that ectopically expressed NIK both spontaneously forms oligomers and displays a high level of constitutive activity. Analysis of a series of NIK deletion mutants indicates that multiple subregions of the kinase participate in the formation of these NIK-NIK oligomers. NIK also physically assembles with downstream IKKalpha ; however, this interaction is mediated through a discrete C-terminal domain within NIK located between amino acids 735 and 947. When expressed alone, this C-terminal NIK fragment functions as a potent inhibitor of TNF-alpha -mediated induction of NF-kappa B and alone is sufficient to disrupt the physical association of NIK and IKKalpha . Together, these findings provide new insights into the molecular basis for TNF-alpha signaling, suggesting an important role for heterotypic and possibly homotypic interactions of NIK in this response.

* Corresponding author. Mailing address: Gladstone Institute of Virology and Immunology, P.O. box 419100, San Francisco, CA 94141-9100. Phone: (415) 695-3800. Fax: (415) 826-1817. E-mail: Warner_Greene{at}quickmail.ucsf.edu.

Molecular and Cellular Biology, October 1998, p. 5899-5907, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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