New Regulatory Role for NF-κB Precursor

Science's STKE  08 Apr 2003:
Vol. 2003, Issue 177, pp. tw135-TW135
DOI: 10.1126/stke.2003.177.tw135

The NF-kappa B (NF-κB) transcription factors, which have critical roles in immune function, are translated as large precursor proteins that are proteolytically processed to form the mature transcription factor. However, expression of p50, the mature form of NF-κB1, does not fully compensate for loss of the p105 precursor form, which suggests that the precursor may have a distinct function of its own. Waterfield et al. now propose that one such function of p105 is to interact directly with and to inhibit the MAP (mitogen-activated protein) kinase kinase kinase Tpl2. Toll-like receptors recognize infection by binding bacterially derived molecules like lipopolysaccharide (LPS). The Tpl2 protein kinase participates in signaling from Toll-like receptors to the nucleus. Waterfield et al. report that LPS-induced activation of Tpl2 is lost in macrophages from mice lacking p105. The authors confirmed previous reports that p105 interacts with the Tpl2 protein in vivo. Expression of both proteins in 293 cells indicated that the interaction stabilizes the Tpl2 protein, but also inhibits the kinase activity of Tpl2. Tpl2 protein isolated from wild-type macrophages in a complex with p105 lacked kinase activity, and stimulation of cells with LPS caused release of the kinase. The authors' model expands the role of NF-κB1 in LPS signaling from the traditional one of activating target genes (mediated by the mature form) to one in which the precursor form of the transcription factor modulates upstream signals in a distinct gene-regulatory pathway mediated by MAP kinases.

M. R. Waterfield, M. Zhang, L. P. Norman, S.-C. Sun. NF-κB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase. Mol. Cell 11, 685-694 (2003). [Online Journal]