In mammals, the canonical nuclear factor kappaB (NF-kappaB) signaling pathway activated in response to infections is based on degradation of IkappaB inhibitors. This pathway depends on the IkappaB kinase (IKK), which contains two catalytic subunits, IKKalpha and IKKbeta. IKKbeta is essential for inducible IkappaB phosphorylation and degradation, whereas IKKalpha is not. Here we show that IKKalpha is required for B cell maturation, formation of secondary lymphoid organs, increased expression of certain NF-kappaB target genes, and processing of the NF-kappaB2 (p100) precursor. IKKalpha preferentially phosphorylates NF-kappaB2, and this activity requires its phosphorylation by upstream kinases, one of which may be NF-kappaB-inducing kinase (NIK). IKKalpha is therefore a pivotal component of a second NF-kappaB activation pathway based on regulated NF-kappaB2 processing rather than IkappaB degradation.

IκB kinase (IKK) is a key mediator of NF‐κB activation induced by various immunological signals. In T cells and most other cell types, the primary target of IKK is a labile inhibitor of NF‐κB, IκBα, which is responsible for the canonical NF‐κB activation. Here, we show that in T cells infected with the human T‐cell leukemia virus (HTLV), IKKα is targeted to a novel signaling pathway that mediates processing of the nfκb2 precursor protein p100, resulting in active production of the NF‐κB subunit, p52. This pathogenic action is mediated by the HTLV‐encoded oncoprotein Tax, which appears to act by physically recruiting IKKα to p100, triggering phosphorylation‐dependent ubiquitylation and processing of p100. These findings suggest a novel mechanism by which Tax modulates the NF‐κB signaling pathway.

The processing of the nf b2 gene product p100 to generate p52 is a regulated event, which is important for the instrumental function of NF-B. We previously demonstrated that this tightly controlled event is regulated positively by NF-B-inducing kinase (NIK) and its downstream kinase, I B kinase ␣ (IKK␣). However, the precise mechanisms by which NIK and IKK␣ induce p100 processing remain unclear. Here, we show that, besides activating IKK␣, NIK also serves as a docking molecule recruiting IKK␣ to p100. This novel function of NIK requires two specific amino acid residues, serine 866 and serine 870, of p100 that are known to be essential for inducible processing of p100. We also show that, after being recruited into p100 complex, activated IKK␣ phosphorylates specific serines located in both N-and Cterminal regions of p100 (serines 99, 108, 115, 123, and 872). The phosphorylation of these specific serines is the prerequisite for ubiquitination and subsequent processing of p100 mediated by the ␤-TrCP ubiquitin ligase and 26 S proteasome, respectively. These results highlight the critical but different roles of NIK and IKK␣ in regulating p100 processing and shed light on the mechanisms mediating the tight control of p100 processing. These data also provide the first evidence for explaining why overexpression of IKK␣ or its activation by many other stimuli such as tumor necrosis factor and mitogens fails to induce p100 processing.