CPEB regulation of TAK1 synthesis mediates cytokine production and the inflammatory immune response

Mol Cell Biol. 2015 Feb;35(3):610-8. doi: 10.1128/MCB.00800-14. Epub 2014 Dec 1.


The cytoplasmic-element-binding (CPEB) protein is a sequence-specific RNA-binding protein that regulates cytoplasmic polyadenylation-induced translation. In mouse embryo fibroblasts (MEFs) lacking CPEB, many mRNAs encoding proteins involved in inflammation are misregulated. Correlated with this aberrant translation in MEFs, a macrophage cell line depleted of CPEB and treated with lipopolysaccharide (LPS) to stimulate the inflammatory immune response expresses high levels of interleukin-6 (IL-6), which is due to prolonged nuclear retention of NF-κB. Two proteins involved in NF-κB nuclear localization and IL-6 expression, IκBα and transforming growth factor beta-activated kinase 1 (TAK1), are present at excessively low and high steady-state levels, respectively, in LPS-treated CPEB-depleted macrophages. However, only TAK1 has an altered synthesis rate that is CPEB dependent and CPEB/TAK1 double depletion alleviates high IL-6 production. Peritoneal macrophages isolated from CPEB knockout (KO) mice treated with LPS in vitro also have prolonged NF-κB nuclear retention and produce high IL-6 levels. LPS-injected CPEB KO mice secrete prodigious amounts of IL-6 and other proinflammatory cytokines and exhibit hypersensitivity to endotoxic shock; these effects are mitigated when the animals are also injected with (5Z)-7-oxozeaenol, a potent and specific inhibitor of TAK1. These data show that CPEB control of TAK1 mRNA translation mediates the inflammatory immune response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Inflammation / immunology
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Kinase Kinases / immunology
  • MAP Kinase Kinase Kinases / metabolism*
  • Male
  • Mice
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • RNA-Binding Proteins / immunology
  • RNA-Binding Proteins / metabolism*
  • Regulatory Sequences, Nucleic Acid
  • Signal Transduction / immunology*
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism


  • CPEB protein, mouse
  • Interleukin-6
  • Lipopolysaccharides
  • NF-kappa B
  • RNA-Binding Proteins
  • Tumor Necrosis Factor-alpha
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7