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Molecular and Cellular Biology, September 2002, p. 6573-6581, Vol. 22, No. 18
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.18.6573-6581.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Carboxyl-Terminal Region of I{kappa}B Kinase {gamma} (IKK{gamma}) Is Required for Full IKK Activation

Constantin Makris,1,{dagger} Jaclyn L. Roberts,2 and Michael Karin1*

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, California 92093-0636,1 Department of Obstetrics and Gynecology, State University of New York Health Science Center, Brooklyn, New York 112032

Received 18 March 2002/ Returned for modification 24 April 2002/ Accepted 4 June 2002

I{kappa}B kinase {gamma} (IKK{gamma}) (also known as NEMO, Fip-3, and IKKAP-1) is the essential regulatory component of the IKK complex; it is required for NF-{kappa}B activation by various stimuli, including tumor necrosis factor alpha (TNF-{alpha}), interleukin 1 (IL-1), phorbol esters, lipopolysaccharides, and double-stranded RNA. IKK{gamma} is encoded by an X-linked gene, deficiencies in which may result in two human genetic disorders, incontinentia pigmenti (IP) and hypohidrotic ectodermal dysplasia with severe immunodeficiency. Subsequent to the linkage of IKK{gamma} deficiency to IP, we biochemically characterized the effects of a mutation occurring in an IP-affected family on IKK activity and NF-{kappa}B signaling. This particular mutation results in premature termination, such that the variant IKK{gamma} protein lacks its putative C-terminal Zn finger and, due to decreased mRNA stability, is underexpressed. Correspondingly, IKK and NF-{kappa}B activation by TNF-{alpha} and, to a lesser extent, IL-1 are reduced. Mutagenesis of the C-terminal region of IKK{gamma} was performed in an attempt to define the role of the putative Zn finger and other potential functional motifs in this region. The mutants were expressed in IKK{gamma}-deficient murine embryonic fibroblasts (MEFs) at levels comparable to those of endogenous IKK{gamma} in wild-type MEFs and were able to associate with IKK{alpha} and IKKß. Substitution of two leucines within a C-terminal leucine zipper motif markedly reduced IKK activation by TNF-{alpha} and IL-1. Another point mutation resulting in a cysteine-to-serine substitution within the putative Zn finger motif affected IKK activation by TNF-{alpha} but not by IL-1. These results may explain why cells that express these or similar mutant alleles are sensitive to TNF-{alpha}-induced apoptosis despite being able to activate NF-{kappa}B in response to other stimuli.

* Corresponding author. Mailing address: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0636. Phone: (858) 534-1361. Fax: (858) 534-8158. E-mail: karinoffice{at}ucsd.edu.

{dagger} Present address: Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada & Co., Kirkland, Quebec, Canada H9H 3L1.

Molecular and Cellular Biology, September 2002, p. 6573-6581, Vol. 22, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.18.6573-6581.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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