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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.

Original publication

DOI

10.1093/nar/gkw474

Type

Journal article

Journal

Nucleic Acids Res

Publication Date

06/09/2016

Volume

44

Pages

7418 - 7440

Keywords

Adaptor Proteins, Signal Transducing, Animals, Bone Marrow Cells, Cell Survival, Cross-Linking Reagents, Cytokines, Feedback, Physiological, Gene Expression Regulation, High-Throughput Screening Assays, Humans, Immunoprecipitation, Inflammation, Intracellular Signaling Peptides and Proteins, Lipopolysaccharides, Macrophages, Mice, NF-kappa B, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, RNA, Messenger, RNA-Binding Proteins, Substrate Specificity, Transcriptome