Phosphorylation-dependent association of the G4-1/G5PR regulatory subunit with IKKβ negatively modulates NF-κB activation through recruitment of protein phosphatase 5

Chao Wei Chiang, Wei Kuang Liu, Chi Wu Chiang, Chen Kung Chou

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The transcription factor NF-κB (nuclear factor κB) co-ordinates various gene expressions in response to diverse signals and is a critical regulator of inflammation and innate immunity. Several negative regulators of NF-κB have been identified as downstream targets of NF-κB and function as a feedback control of NF-κB activation. A few protein phosphatases have also been shown to inactivate NF-κB activation. However, little is known about how protein phosphatases detect and respond to NF-κB activation. In the present study, we report a regulatory subunit of PP5 (protein phosphatase 5),G4-1, that physically interactswith IKKβ [IκB (inhibitor of NF-κB) kinase β] and negatively regulates NF-κB activation. The association of G4-1 with IKKβ depends on the kinase activity of IKKβ. Mapping of the G4-1-binding domain of IKKβ reveals that the serine-rich domain in the C-terminus of IKKβ is required for G4-1 binding. When seven autophosphorylated serine residues in this domain were mutated to alanine, the mutant form of IKKβ lost its ability to bind G4-1 and was more potent than the wild-type kinase to activate NF-κB. Knockdown of G4-1 enhanced TNFα (tumour necrosis factor α)-induced NF-κB activity, and knockdown of PP5 totally abolished the inhibitory activity of G4-1 on NF-κB activation. The results of the present study suggest that G4-1 functions as an adaptor to recruit PP5 to the phosphorylated C-terminus of activated IKKβ and to down-regulate the activation of IKKβ.

Original languageEnglish
Pages (from-to)187-196
Number of pages10
JournalBiochemical Journal
Volume433
Issue number1
DOIs
Publication statusPublished - 2011 Jan 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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