Deactivation of the kinase IKK by CUEDC2 through recruitment of the phosphatase PP1

Nat Immunol. 2008 May;9(5):533-41. doi: 10.1038/ni.1600. Epub 2008 Mar 23.

Abstract

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 IKKalpha and IKKbeta and repressed activation of the transcription factor NF-kappaB 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism
  • Carrier Proteins / immunology
  • Carrier Proteins / metabolism*
  • Catalytic Domain
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Female
  • Humans
  • I-kappa B Kinase / chemistry
  • I-kappa B Kinase / metabolism*
  • Inflammation / immunology
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / genetics
  • Macrophages / immunology
  • Macrophages / metabolism
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Phosphatase 1 / metabolism*
  • Repressor Proteins / immunology
  • Repressor Proteins / metabolism*
  • Up-Regulation

Substances

  • Antigens, Differentiation
  • CUEDC2 protein, human
  • CUEDC2 protein, mouse
  • Carrier Proteins
  • Cell Cycle Proteins
  • Interleukin-6
  • Membrane Proteins
  • NF-kappa B
  • Repressor Proteins
  • I-kappa B Kinase
  • PPP1R15A protein, human
  • Protein Phosphatase 1