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.
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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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