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Nucleic Acids Res. 2016 Sep 6;44(15):7418-40. doi: 10.1093/nar/gkw474. Epub 2016 May 24.

The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation.

Author information

1
Institute of Physiological Chemistry, Medical School Hannover (MHH), 30625 Hannover, Germany Tiedje.Christopher@mh-hannover.de.
2
Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK manuel.diaz-munoz@babraham.ac.uk.
3
Institute of Physiological Chemistry, Medical School Hannover (MHH), 30625 Hannover, Germany.
4
Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK.
5
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; and Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.

Abstract

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.

PMID:
27220464
PMCID:
PMC5009735
DOI:
10.1093/nar/gkw474
[Indexed for MEDLINE]
Free PMC Article

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