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B Kinase 
Impairs Lipopolysaccharide- and TNF-Mediated NF-B Activation through Inhibiting Phosphorylation of the I-B Kinase 
Activation Loop1
,
* Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences,
Department of Periodontics, School of Dentistry,
Program in Cellular and Molecular Biology, and
Department of Biological Chemistry, School of Medicine, University of Michigan, Ann Arbor, MI 48109
The activation of the I-
B kinase (IKK) complex by TNF or LPS stimulates phosphorylation and degradation of I-B
, leading to the nuclear translocation of NF-B. The IKK complex is mainly composed of two catalytic subunits, IKK and IKK
, and a chaperon subunit IKK
. Although IKK does not have catalytic activity, it is essential for IKK activation induced by multiple stimuli. Importantly, the key residue cysteine 417 at the zinc finger domain of IKK has been found to be mutated to arginine (IKKC417R) in a human genetic disorder called the anhydrotic ectodermal dysplasia with immunodeficiency. To understand the underlying mechanisms of immunodeficiency, we examined whether the IKKC417R mutant modified IKK activation and NF-B transcription stimulated by LPS or TNF in human monocytes. We found that overexpression of IKKC417R severely impaired LPS- and TNF-induced I-B phosphorylation and degradation in a dominant-negative fashion. Also, LPS- and TNF-induced NF-B transcription was inhibited by IKKC417R. The reconstitution of IKK, but not IKKC417R, in IKK-deficient cells restored NF-B signaling, indicating the zinc finger structure of IKK plays a key role in IKK activation. Moreover, C417R mutation in IKK abolished both LPS- and TNF-induced phosphorylation of the activation loop of IKK. Collectively, our results indicated that the zinc finger structure of IKK plays a key role in LPS- and TNF-induced NF-B activation. The anhydrotic ectodermal dysplasia with immunodeficiency patients’ immunodeficiency may be associated with NF-B defect in response to bacterial stimulation.
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