RACK1 Modulates NF-κB Activation by Interfering With the Interaction Between TRAF2 and the IKK Complex

Cell Res. 2014 Mar;24(3):359-71. doi: 10.1038/cr.2013.162. Epub 2013 Dec 10.

Abstract

The transcription factor NF-κB plays a pivotal role in innate immunity in response to a variety of stimuli, and the coordinated regulation of this pathway determines the proper host responses to extracellular signals. In this study, we identified RACK1 as a novel negative regulator of NF-κB signaling, NF-κB-mediated cytokine induction and inflammatory reactions. RACK1 physically associates with the IKK complex in a TNF-triggered manner. This interaction interferes with the recruitment of the IKK complex to TRAF2, which is a critical step for IKK phosphorylation and subsequent activation triggered by TNF. By modulating the interaction between TRAF2 and IKK, RACK1 regulates the levels of NF-κB activation in response to different intensities of stimuli. Our findings suggest that RACK1 plays an important role in controlling the sensitivity of TNF-triggered NF-κB signaling by regulating IKK activation and provide new insight into the negative regulation of inflammatory reactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytokines / metabolism
  • Enzyme Activation / drug effects
  • GTP-Binding Proteins / antagonists & inhibitors
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • I-kappa B Kinase / chemistry
  • I-kappa B Kinase / metabolism*
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / metabolism*
  • Phosphorylation / drug effects
  • Protein Binding
  • Protein Structure, Tertiary
  • RNA Interference
  • RNA, Small Untranslated / metabolism
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction / drug effects
  • TNF Receptor-Associated Factor 2 / chemistry
  • TNF Receptor-Associated Factor 2 / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Cytokines
  • NF-kappa B
  • Neoplasm Proteins
  • RACK1 protein, human
  • RNA, Small Untranslated
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • I-kappa B Kinase
  • GTP-Binding Proteins