A New Role for a Kinase Subunit

Once, researchers thought that only the kinase IKKb--and not its second catalytic subunit, IKKa--had a direct role in activating NF-kB, the much-studied transcription factor that is implicated in activating genes responsible for inflammatory responses and apoptosis.1 However, new research by Michael Karin, professor of pharmacology at the University of California, San Diego, and colleagues at Pennsylvania State University and the University of Ulm, Germany, have demonstrated the role of IKKa in a second NF-kB activation pathway.2 This research, says Karin, is important because the NF-kB pathway is involved in acute and chronic inflammatory diseases and cancer. Pharmaceutical companies, he explains, want to find general IKK inhibitors or IKKb subunit inhibitors, even though IKKb inhibition leads to apoptosis sensitivity induced by tumor necrosis factor and immune deficiencies. "However, if you inhibit IKKa, based on our results, the effects are much milder and much more specific--you block the maturation of B cells, and you block certain antibody-mediated responses. There are diseases where this is quite desirable, autoimmune diseases where the pathology is caused by autoantibodies produced by B cells," Karin says. NF-kB is important in the development and function of lymphoid cells,3 so one way to examine IKKa's role in NF-kB activation would be to examine B-cell markers in IKKa-deficient lymphoid cells. Unfortunately, IKKa knockout mice die within minutes of birth.4 To overcome this problem, Karin and colleagues generated chimeric mice whose lymphoid and myeloid compartment cells were removed through radiation and reconstructed with wild-type or IKKa-deficient stem cells. They found that IKKa is required for B-cell maturation but didn't observe a corresponding defect in the induction of standard NF-kB DNA's binding activity in the IKKa-deficient B cells. Instead, they found that the processing of one of the transcription factor's proteins, NF-kB2, was hampered in IKKa-deficient cells. This indicates that, while IKKa is not required in the canonical NF-kB pathway, it is involved in a second activation pathway based on inducible production of p52, one of the subunits of NF-kB. This subunit is produced by proteolytic processing of the NF-kB2, p100 precursor protein. "That was not really anticipated," says Karin. Although similar in sequence and structure, the alpha and beta subunits of IKK have different roles.1 In unstimulated B cells, NF-kB exists in the cytoplasm in a complex with an inhibitor protein, I*B. IKKb phosphorylates the inhibitor, inducing its degradation. The b subunit therefore plays a direct role in the transcription factor's activation. On the other hand, previous work on IKKa has demonstrated the protein's requirement during skin and skeletal development.4 The findings also help define the NF-kB activation pathway's evolution. The newly discovered pathway resembles one regulated by the Drosophila IKK homolog, which is required to process the NF-kB2-like precursor Relish. "In mammals we showed that one catalytic subunit, IKKb, is required for the canonical NF-kB activation pathway ... but the other subunit, IKKa, can regulate NF-kB2 processing, similar to the Drosophila IKK." This evidence suggests that the IKK complex's ancient form was not an I*B kinase and that I*B's degradation in the transcription factor's activation pathway might be a modern adaptation. Aileen Constans can be contacted at aconstans@the-scientist.com References 1. M.J. May, S. Ghosh, "IkB kinases: Kinsmen with different crafts," Science, 284:271, 1999. 2. U. Senftleben et al., "Activation by IKKa of a second, evolutionary conserved, NF-kB signaling pathway," Science, 293:1495-9, Aug. 24, 2001. 3.L. Yin et al., "Defective lymphotoxin-beta receptor-induced NF-kB transcriptional activity in NIK-deficient mice," Science, 291:2162-5, 2001. 4. Y. Hu et al., "Abnormal morphogenesis but intact IKK activation in mice lacking the IKKa subunit of I*B kinase," Science, 284:316-20, 1999.

A New Role for a Kinase Subunit

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