NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100.
Processing of the nf(kappa)b2 gene product p100 to generate p52 is an important step in NF-kappaB regulation. We show that this step is negatively regulated by a processing-inhibitory domain (PID) within p100 and positively regulated by the NF-kappaB-inducing kinase (NIK). While the PID suppresses the constitutive processing of p100, NIK induces p100 processing by stimulating site-specific phosphorylation and ubiquitination of this precursor protein. Further, a natural mutation of the gene encoding NIK in alymphoplasia (aly) mice cripples the function of NIK in p100 processing, causing a severe defect in p52 production. These data suggest that NIK is a specific kinase regulating p100 processing and explain why the aly and nf(kappa)b2 knockout mice exhibit similar immune deficiencies.
Xiao
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Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Harhaj
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EW
Sun
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SC
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008817:Mice, Mutant Strains; D008970:Molecular Weight; D009154:Mutation; D016328:NF-kappa B / Q000737:chemistry* / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D014162:Transfection; D014452:Ubiquitins / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D010768:Phosphoserine; D017346:Protein Serine-Threonine Kinases; D014452:Ubiquitins; D000097782:NF-kappaB-Inducing Kinase