Despite rapid progress in elucidating the molecular mechanisms of activation of the kinase IKK, the processes that regulate IKK deactivation are still unknown. Here we demonstrate that CUE domain–containing 2 (CUEDC2) interacted with IKKα and IKKβ and repressed activation of the transcription factor NF-κB by decreasing phosphorylation and activation of IKK. Notably, CUEDC2 also interacted with GADD34, a regulatory subunit of protein phosphatase 1 (PP1). We found that IKK, CUEDC2 and PP1 existed in a complex and that IKK was released from the complex in response to inflammatory stimuli such as tumor necrosis factor. CUEDC2 deactivated IKK by recruiting PP1 to the complex. Therefore, CUEDC2 acts as an adaptor protein to target IKK for dephosphorylation and inactivation by recruiting PP1.
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We thank Z.G. Liu (National Cancer Institute, National Institutes of Health) for human IKKα and IKKβ plasmids and TRAF2-deficient MEFs; M.W. Mayo (University of Virginia) for the p65 expression plasmid; X. Lin (Anderson Cancer Center) for the RIP expression vector; X.X. Li (Cleveland Clinic Foundation) for construction of pE-selectin-Luc; G. Haegeman (University of Gent, Gent) for the pIL-6-Luc plasmid; and Z.G. Liu for discussions and technical help. Supported by the National Natural Science Foundation of China (30525021, 30672357, 30500583 and 30321003), the Major State Basic Research Development Program of China (973 Program; 2004CB518800) and the National High Technology Research and Development Program of China (2006AA02Z340).
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Li, HY., Liu, H., Wang, CH. et al. Deactivation of the kinase IKK by CUEDC2 through recruitment of the phosphatase PP1. Nat Immunol 9, 533–541 (2008). https://doi.org/10.1038/ni.1600
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