title: CPEB regulation of TAK1 synthesis mediates cytokine production and the inflammatory immune response.
abstract: 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.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Ivshina
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Ilya M
authors.initials: IM
authors.lastname: Alexandrov
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Anastassiia
authors.initials: A
authors.lastname: Vertii
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Doxsey
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA joel.richter@umassmed.edu.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Richter
mesh_terms: D000818:Animals; D007249:Inflammation / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7; D014157:Transcription Factors; D039221:mRNA Cleavage and Polyadenylation Factors
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C490387:Cpeb1 protein, mouse; D014157:Transcription Factors; D039221:mRNA Cleavage and Polyadenylation Factors