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The IKKβ Subunit of IB Kinase (IKK) is Essential for Nuclear Factor B Activation and Prevention of Apoptosis

Zhi-Wei Li^*, Wenming Chu^*, Yinling Hu^*, Mireille Delhase^*, Tom Deerinck, Mark Ellisman, Randall Johnson, and Michael Karin^*

From the ^* Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, Department of Biology, and Department of Neuroscience, University of California, San Diego, La Jolla, California 92093-0636

The IB kinase (IKK) complex is composed of three subunits, IKK, IKKβ, and IKK (NEMO). While IKK and IKKβ are highly similar catalytic subunits, both capable of IB phosphorylation in vitro, IKK is a regulatory subunit. Previous biochemical and genetic analyses have indicated that despite their similar structures and in vitro kinase activities, IKK and IKKβ have distinct functions. Surprisingly, disruption of the Ikk locus did not abolish activation of IKK by proinflammatory stimuli and resulted in only a small decrease in nuclear factor (NF)-B activation. Now we describe the pathophysiological consequence of disruption of the Ikkβ locus. IKKβ-deficient mice die at mid-gestation from uncontrolled liver apoptosis, a phenotype that is remarkably similar to that of mice deficient in both the RelA (p65) and NF-B1 (p50/p105) subunits of NF-B. Accordingly, IKKβ-deficient cells are defective in activation of IKK and NF-B in response to either tumor necrosis factor or interleukin 1. Thus IKKβ, but not IKK, plays the major role in IKK activation and induction of NF-B activity. In the absence of IKKβ, IKK is unresponsive to IKK activators.

Key Words: inflammation • tumor necrosis factor • interleukin 1 • knockout mice • signal transduction

Y. Hu was supported by a postdoctoral fellowship from the Arthritis Foundation. This work was supported by grants from the National Institutes of Health (AI43477, ES04151, AG05131, and RR04050) and the Department of Energy (DE-FG03-86ER60429). M. Karin is the Frank and Else Schilling-American Cancer Society Research Professor.

Abbreviations used: EF, embryonic fibroblast; EMSA, electrophoretic mobility shift assay; ES, embryonic stem; H&E, hematoxylin and eosin; IKK, IB kinase; NF, nuclear factor; NIK, NF-B inducing kinase; TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling.

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