Research ArticleImmunology

Noncanonical NF-κB Signaling Is Limited by Classical NF-κB Activity

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Science Signaling  04 Feb 2014:
Vol. 7, Issue 311, pp. ra13
DOI: 10.1126/scisignal.2004557

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Two Pathways to Immunodeficiency

Two nuclear factor κB (NF-κB) signaling pathways with distinct target genes are activated by immune stimuli. Gray et al. found that cells from immunodeficient patients with mutations in NEMO, a component thought to be required to activate only the classical NF-κB pathway, exhibited activity through the noncanonical NF-κB pathway even under unstimulated conditions. This aberrant noncanonical pathway activity was associated with an increase in the abundance of a kinase that is necessary to activate the noncanonical NF-κB pathway, but that is normally degraded in unstimulated cells. Introduction of wild-type, but not ID-associated mutant, NEMO into NEMO-deficient cells inhibited the noncanonical pathway, which suggests that the NEMO-containing complex that activates the classical NF-κB pathway also limits the activity of the noncanonical pathway.