The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation
| Autor: | Christopher Tiedje, Kathrin Laaß, Matthias Gaestel, Perry J. Blackshear, Manuel D. Díaz-Muñoz, Helena Ahlfors, Martin R Turner, Philipp Trulley |
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| Přispěvatelé: | Turner, Martin [0000-0002-3801-9896], Apollo - University of Cambridge Repository |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides Cell Survival IER3 Tristetraprolin RNA-binding protein Bone Marrow Cells Biology Protein Serine-Threonine Kinases Substrate Specificity 03 medical and health sciences Mice hemic and lymphatic diseases Gene expression Genetics Transcriptional regulation Protein biosynthesis ZFP36 Animals Humans Immunoprecipitation heterocyclic compounds RNA Messenger Phosphorylation neoplasms Adaptor Proteins Signal Transducing Feedback Physiological Inflammation Macrophages Intracellular Signaling Peptides and Proteins NF-kappa B RNA-Binding Proteins respiratory system Molecular biology High-Throughput Screening Assays 030104 developmental biology Cross-Linking Reagents Gene Expression Regulation Cytokines RNA Transcriptome ICLIP therapeutics Protein Binding |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 |
| Popis: | RNA-binding proteins (RBPs) facilitate post-transcriptional control of eukaryotic gene expression at multiple levels. The RBP tristetraprolin (TTP/Zfp36) is a signal-induced phosphorylated anti-inflammatory protein guiding unstable mRNAs of pro-inflammatory proteins for degradation and preventing translation. Using iCLIP, we have identified numerous mRNA targets bound by wild-type TTP and by a non-MK2-phosphorylatable TTP mutant (TTP-AA) in 1 h LPS-stimulated macrophages and correlated their interaction with TTP to changes at the level of mRNA abundance and translation in a transcriptome-wide manner. The close similarity of the transcriptomes of TTP-deficient and TTP-expressing macrophages upon short LPS stimulation suggested an effective inactivation of TTP by MK2, whereas retained RNA-binding capacity of TTP-AA to 3'UTRs caused profound changes in the transcriptome and translatome, altered NF-κB-activation and induced cell death. Increased TTP binding to the 3'UTR of feedback inhibitor mRNAs, such as Ier3, Dusp1 or Tnfaip3, in the absence of MK2-dependent TTP neutralization resulted in a strong reduction of their protein synthesis contributing to the deregulation of the NF-κB-signaling pathway. Taken together, our study uncovers a role of TTP as a suppressor of feedback inhibitors of inflammation and highlights the importance of fine-tuned TTP activity-regulation by MK2 in order to control the pro-inflammatory response. |
| Databáze: | OpenAIRE |
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