The I B Kinase: A Master Regulator of NF- B, Innate Immunity, and Epidermal Differentiation

Originally thought to be a B-cell-specific transcriptionfactor involved in regulation of the immunoglobulin κlight-chain gene (Sen and Baltimore 1986), NF-κB hasemerged as a ubiquitous, evolutionarily conserved transcription factor whose activity is rapidly induced in response to (mostly) proinflammatory stimuli (Baeuerleand Baltimore 1996). In most cell types, NF-κB, a heterogeneous collection of dimeric proteins composed ofmembers of the Rel family, resides in the cytoplasm because it is bound to members of the IκB family (for review, see Siebenlist et al. 1994; Baldwin 1996; Ghosh etal. 1998). The IκBs, of which there are several, directlybind to the DNA-binding and dimerization domain of theRel proteins, known as the Rel homology domain (RHD),interfering with the function of the nuclear localizationsignal (NLS) present near the carboxyl terminus of theRHD ( Siebenlist et al. 1994; Baldwin 1996; Ghosh et al.1998). According to recently solved three-dimensionalstructures of the core of IκBα in complex with the RHDsof the major NF-κB components, p50/NF-κB1 andp65/RelA, the amino terminus of the IκB core, which iscomposed of six to seven ankyrin repeats, is positionednext to the NLS and most likely sterically hinders thebinding of karyopherins to the latter (Huxford et al. 1998;Jacobs and Harrison 1998). Therefore, the only way toget NF-κB to its site of action, the nucleus, is to disruptthe NF-κB:IκB complex. Curiously, nature has come upwith only one major and unusually complex pathway toaccomplish disruption of the NF-κB:IκB complex in response to extracellular stimuli. This pathway involves thecoordinated action of a very large number of proteins (atleast 20) and an even larger number of ATP molecules. Itis estimated that the energy cost of activating NF-κB isalmost as high as the one invested in synthesis of its components. Despite this complexity, NF-κB activation occurs very rapidly, making it an ideal signaling system forproinflammatory stimuli, which trigger innate immuneresponses— the first line of defense against bacterial,fungal, and viral infections. Efficient defense against microbial infections requires rapid signaling responses thatdo not depend on de novo protein synthesis, yet are capable of coordinating the induction of a large number ofgenes, whose products cannot be constitutively expresseddue to potential autotoxicity. Due to this toxicity problem, an efficient signaling system should also feature abuilt-in ability to turn itself off when no longer needed.The NF-κB system has it all...