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J Biol Chem. 2003 May 30;278(22):19642-8. Epub 2003 Mar 25.

In vivo identification of inducible phosphoacceptors in the IKKgamma/NEMO subunit of human IkappaB kinase.

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  • 1Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0295, USA.


Transcription factor NF-kappaB plays a pivotal regulatory role in the genetic programs for cell cycle progression and inflammation. Nuclear translocation of NF-kappaB is controlled by an inducible protein kinase called IKK, which earmarks cytoplasmic inhibitors of NF-kappaB for proteolytic destruction. IKK contains two structurally related catalytic subunits termed IKKalpha and IKKbeta as well as a noncatalytic subunit called IKKgamma/NEMO. Mutations in the X-linked gene encoding IKKgamma can interfere with NF-kappaB signaling and lead to immunodeficiency disease. Although its precise mechanism of action remains unknown, IKKgamma is phosphorylated in concert with the induction of NF-kappaB by the viral oncoprotein Tax and the proinflammatory cytokine tumor necrosis factor alpha (TNF). We now demonstrate that TNF-induced phosphorylation of IKKgamma is blocked in cells deficient for IKKbeta but not IKKalpha. Phosphopeptide-mapping experiments with metabolically radiolabeled cells indicate that IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376 following the enforced expression of either the Tax oncoprotein or the type 1 TNF receptor. Inducible phosphorylation of IKKgamma is attenuated following the deletion of its COOH-terminal zinc finger domain (amino acids 397-419), a frequent target for mutations that occur in IKKgamma-associated immunodeficiencies. As such, IKKbeta-mediated phosphorylation of IKKgamma at these specific serine targets may facilitate proper regulation of NF-kappaB signaling in the immune system.

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