Inflammation: Stopping before the damage is done
Overexpression of CUE-domain-containing protein 2 (CUEDC2) inhibits the phosphorylation of IKK and IKK in response to tumor-necrosis factor signaling, thereby preventing the nuclear translocation of NF- B.
The activation of nuclear factor-B (NF-B) in response to cytokine signalling is a powerful mechanism for initiating an inflammatory immune response, but as is often the case in the immune system, with great power comes the potential to cause great damage. Li and colleagues now describe another element of the control systems that are responsible for preventing inflammatory damage to the host.
NF-B is normally maintained in an inactive state in the cytoplasm by inhibitor of NF-B (IB) proteins. In response to pro-inflammatory cytokine signalling, the IB kinase (IKK) complex is activated by phosphorylation; in turn, activation of the IKK complex — through the phosphorylation of IB proteins and their subsequent ubiquitylation and proteasomal degradation — results in the release of NF-B 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 IKK and IKK 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 IKK and IKK in response to tumour-necrosis factor (TNF) signalling, and thereby inhibits the kinase activity of the IKK complex, the degradation of IB proteins and the nuclear translocation of NF-B. Conversely, small interfering RNA (siRNA)-mediated knockdown of CUEDC2 expression led to prolonged IKK activation.
TNF treatment of cells resulted in the rapid recruitment of IKK but not CUEDC2 to the TNF receptor signalling complex, which indicates that the IKK complex dissociates from its inhibitory interaction with CUEDC2 in response to TNF signalling. However, the interaction between IKK and CUEDC2 was completely restored by 30 minutes after TNF treatment; as the IKK complex dissociates from the TNF receptor, it rebinds CUEDC2.
So how does CUEDC2 inhibit the IKK complex? The authors found that the IKK–CUEDC2 complex co-precipitates with the regulatory GADD34 subunit and catalytic PP1C subunit of protein phosphatase 1 (PP1), and that CUEDC2 is indispensable for the formation of a complex containing both IKK and PP1. Expression of CUEDC2, GADD34 and PP1C together (but not GADD34 and PP1C without CUEDC2) completely abrogated IKK phosphorylation and repressed TNF-induced NF-B activity. Therefore, CUEDC2 mediates the dephosphorylation (and hence inactivation) of the IKK complex by functioning as an adaptor protein to recruit the phosphatase PP1.
The physiological relevance of CUEDC2 in the regulation of IKK activity was shown by its inhibitory effect on the NF-B-mediated production of interleukin-6 by macrophages in response to TNF. The authors therefore propose that IKK is maintained in a default inactive state by its interaction with CUEDC2–PP1, which allows for the transient, signal-dependent activation of IKK that is required for a controlled inflammatory response.
Kirsty Minton
References
- Li, H.-Y. et al. Deactivation of the kinase IKK by CUEDC2 through recruitment of the phosphatase PP1. Nature Immunol. 9, 533–541 (2008) | Article | PubMed |
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