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Inflammation

Stopping before the damage is done

Nature Reviews Immunology volume 8, pages 324–325 (2008)Cite this article

NF-κB is normally maintained in an inactive state in the cytoplasm by inhibitor of NF-κB (IκB) proteins. In response to pro-inflammatory cytokine signalling, the IκB kinase (IKK) complex is activated by phosphorylation; in turn, activation of the IKK complex — through the phosphorylation of IκB proteins and their subsequent ubiquitylation and proteasomal degradation — results in the release of NF-κB for translocation to the nucleus. But what returns the IKK complex to an inactive state after cytokine stimulation to prevent an excessive response?

In a series of in vitro and in vivo precipitation experiments, Li and colleagues showed that the catalytic IKK subunits IKKα and IKKβ both interact with CUE-domain-containing protein 2 (CUEDC2), a protein of previously unknown function. Overexpression of CUEDC2 was used to show that this interaction inhibits the phosphorylation of IKKα and IKKβ in response to tumour-necrosis factor (TNF) signalling, and thereby inhibits the kinase activity of the IKK complex, the degradation of IκB proteins and the nuclear translocation of NF-κB. Conversely, small interfering RNA (siRNA)-mediated knockdown of CUEDC2 expression led to prolonged IKK activation.

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ORIGINAL RESEARCH PAPER

  1. Li, H.-Y. et al. Deactivation of the kinase IKK by CUEDC2 through recruitment of the phosphatase PP1. Nature Immunol. 23 March 2008 (doi:10.1038/ni.1600)

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  1. Kirsty Minton
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Minton, K. Stopping before the damage is done. Nat Rev Immunol 8, 324–325 (2008). https://doi.org/10.1038/nri2324

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