| First Author | Ivshina M | Year | 2015 |
| Journal | Mol Cell Biol | Volume | 35 |
| Issue | 3 | Pages | 610-8 |
| PubMed ID | 25452303 | Mgi Jnum | J:224303 |
| Mgi Id | MGI:5662003 | Doi | 10.1128/MCB.00800-14 |
| Citation | Ivshina M, et al. (2015) CPEB regulation of TAK1 synthesis mediates cytokine production and the inflammatory immune response. Mol Cell Biol 35(3):610-8 |
| abstractText | 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-kappaB. Two proteins involved in NF-kappaB nuclear localization and IL-6 expression, IkappaBalpha 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-kappaB 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. |
