Research ArticleBiochemistry

The NF-κB subunit RelB controls p100 processing by competing with the kinases NIK and IKK1 for binding to p100

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Sci. Signal.  27 Sep 2016:
Vol. 9, Issue 447, pp. ra96
DOI: 10.1126/scisignal.aad9413

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Intermolecular competition for activation or inhibition

Noncanonical nuclear factor κB (NF-κB) signaling requires cleavage of the RelB-bound p100 precursor to generate the transcriptionally active p52:RelB heterodimer in a process dependent on the kinases NIK and IKK1. However, p100:RelB dimers also form kappaBsomes, multiprotein complexes that sequester NF-κB subunits to inhibit gene expression. Fusco et al. found that the function of p100 was determined by how RelB was bound to a transitional complex consisting of p100, NIK, and IKK1. If the binding of RelB to p100 displaced NIK and IKK1 from p100, p100 was not phosphorylated or cleaved, and instead, kappaBsomes formed. On the other hand, failure of RelB to displace the kinase complex before p100 phosphorylation resulted in the formation of the active p52:RelB dimer.

Abstract

The heterodimer formed by the nuclear factor κB (NF-κB) subunits p52 and RelB is the product of noncanonical signaling in which the key event is the proteolytic processing of p100 to generate p52. The kinases NF-κB–inducing kinase (NIK) and inhibitor of κB kinase 1 (IKK1; also known as IKKα) are activated during noncanonical signaling and play essential roles in p100 processing. In resting cells, RelB remains associated with unprocessed p100 as a transcriptionally inert p100:RelB complex, which is part of a larger assembly with other NF-κB factors known as the “kappaBsome.” We investigated how these two different RelB-containing complexes with opposing effects on target gene transcription are formed. We found that RelB controls the extent of both p100 processing and kappaBsome formation during noncanonical signaling. Within an apparently “transitional” complex that contains RelB, NIK, IKK1, and p100, RelB and the NIK:IKK1 complex competed with each other for binding to a region of p100. A fraction of p100 in the transitional complex was refractory to processing, which resulted in the formation of the kappaBsome. However, another fraction of p100 protein underwent NIK:IKK1-mediated phosphorylation and processing while remaining bound to RelB, thus forming the p52:RelB heterodimer. Our results suggest that changes in the relative concentrations of RelB, NIK:IKK1, and p100 during noncanonical signaling modulate this transitional complex and are critical for maintaining the fine balance between the processing and protection of p100.

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