The IKK beta subunit of I kappa B kinase (IKK) is essential for nuclear factor kappa B activation and prevention of apoptosis

The I kappa B kinase (IKK) complex is composed of three subunits, IKK alpha , IKK beta, and IKK gamma (NEMO). While IKK alpha and IKK beta are highly s imilar catalytic subunits, both capable of I kappa B phosphorylation in vit ro, IKK gamma is a regulatory subunit. Previous biochemical and genetic ana lyses have indicated that despite their similar structures and in vitro kin ase activities, IKK alpha and IKK beta have distinct functions. Surprisingl y, disruption of the Ikk alpha locus did not abolish activation of IKK by p roinflammatory stimuli and resulted in only a small decrease in nuclear fac tor (NF)-kappa B activation. Now We describe the pathophysiological consequ ence of disruption of the Ikk beta locus. IKK beta-deficient mice die at mi d-gestation from uncontrolled Liver apoptosis, a phenotype that is remarkab ly similar to that of mice deficient in both the RelA (p65) and NF-kappa B1 (p50/p105) subunits of NF-kappa B. Accordingly, IKK beta-deficient cells a re defective in activation of IKK and NF-kappa B in response to either tumo r necrosis factor alpha of interleukin 1. Thus IKK beta, but not IKK alpha, plays the major role in IKK activation and induction of NF-kappa B activit y. In the absence of IKK beta, IKK alpha is unresponsive to IKK activators.