Tristetraprolin as a Therapeutic Target in Inflammatory Disease

Patial, Sonika; Blackshear, Perry J.

doi:10.1016/j.tips.2016.07.002

Cited by 74 publications

(67 citation statements)

References 47 publications

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“…By contrast, suppressing MCPIP1 and roquin 1 activity may be a novel strategy for enhancing cancer immunotherapy or responses to vaccines. Recent studies with a mouse model of regulated TTP overexpression demonstrated a protective effect against several models of immune and inflammatory disease, supporting the potential role of TTP as a therapeutic target 93,94 .…”

Section: Associated Diseases and Therapeutic Potentialmentioning

confidence: 84%

RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins

2016

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Nearly 60 CCCH zinc finger proteins have been identified in humans and mice. These proteins are involved in the regulation of multiple steps of RNA metabolism, including mRNA splicing, polyadenylation, transportation, translation and decay. Several CCCH zinc finger proteins, such as tristetraprolin (TTP), roquin 1 and MCPIP1 (also known as regnase 1), are crucial for many aspects of immune regulation by targeting mRNAs for degradation and modulation of signalling pathways. In this Review, we focus on the emerging roles of CCCH zinc finger proteins in the regulation of immune responses through their effects on cytokine production, immune cell activation and immune homeostasis.

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Section: Associated Diseases and Therapeutic Potentialmentioning

confidence: 84%

RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins

2016

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“…Consistent with such a function, in vitro studies suggest ZPF36 regulates the expression of T-cell-derived cytokines, including IL-2, IFN-γ and IL-17, that mediate lymphocyte homeostasis, microbial response, and inflammation (Lee et al 2012; Ogilvie et al 2009; 2005). The landscape of ZFP36 targets beyond these limited cases in T-cells is unknown, but will be the key to understanding its emerging roles in inflammation, autoimmunity, and malignant cell growth (Patial and Blackshear 2016).…”

Section: Introductionmentioning

confidence: 99%

ZFP36 RNA-binding proteins restrain T-cell activation and anti-viral immunity

Moore

Blachère

Fak

et al. 2018

Preprint

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Dynamic post-transcriptional control of RNA expression by RNA-binding proteins (RBPs) is critical during immune response. ZFP36 RBPs are prominent inflammatory regulators linked to autoimmunity and cancer, but functions in adaptive immunity are less clear. We used HITS-CLIP to define ZFP36 targets in T-cells, which revealed unanticipated actions in regulating T-cell activation, proliferation, and effector functions. Transcriptome and ribosome profiling showed that ZFP36 represses mRNA target abundance and translation, notably through a novel class of AU-rich sites in coding sequence. Functional studies revealed that ZFP36 regulates early T-cell activation kinetics in a cell autonomous manner, by attenuating activation marker expression, limiting T-cell expansion, and promoting apoptosis. Strikingly, loss of ZFP36 in vivo accelerated T-cell responses to acute viral infection, and enhanced anti-viral immunity. These findings uncover a critical role for ZFP36 RBPs in restraining T-cell expansion and effector functions, and suggest ZFP36 inhibition as a novel strategy to enhance immune-based therapies.

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“…This short motif in human TTP was found to interact directly with the human CNOT1 protein (7), and a crystal structure of this interaction demonstrated key residues in the TTP C terminus that have been conserved throughout eukaryotic evolution. Since CNOT1 is a component of the CCR4-NOT complex, a multiprotein complex that contains two 3=-to-5= exonucleases, or deadenylases, this provided an attractive model for the activity of TTP and its family members: after binding to mRNA through the TZF domain, the C-terminal domain would recruit the CCR4-NOT complex to the targeted mRNA, resulting in its accelerated deadenylation and ultimate decay (7,40).…”

Section: Discussionmentioning

confidence: 99%

Importance of the Conserved Carboxyl-Terminal CNOT1 Binding Domain to Tristetraprolin Activity In Vivo

Lai

Stumpo

Wells

et al. 2019

Molecular and Cellular Biology

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Tristetraprolin (TTP) is an anti-inflammatory protein that modulates the stability of certain cytokine/chemokine mRNAs. After initial high-affinity binding to AU-rich elements in 3= untranslated regions of target mRNAs, mediated through its tandem zinc finger (TZF) domain, TTP promotes the deadenylation and ultimate decay of target transcripts. These transcripts and their encoded proteins accumulate abnormally in TTP knockout (KO) mice, leading to a severe inflammatory syndrome. To assess the importance of the highly conserved C-terminal CNOT1 binding domain (CNBD) of TTP to the TTP deficiency phenotype in mice, we created a mouse model in which TTP lacked its CNBD. CNBD deletion mice exhibited a less severe phenotype than the complete TTP KO mice. In macrophages, the stabilization of target transcripts seen in KO mice was partially normalized in the CNBD deletion mice. In cell-free experiments, recombinant TTP lacking its CNBD could still activate target mRNA deadenylation by purified recombinant Schizosaccharomyces pombe CCR4/NOT complexes, although to a lesser extent than full-length TTP. Thus, TTP lacking its CNBD can still act to promote target mRNA instability in vitro and in vivo. These data have implications for TTP family members throughout the eukarya, since species from all four kingdoms contain proteins with linked TZF and CNOT1 binding domains.

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Tristetraprolin as a Therapeutic Target in Inflammatory Disease

Cited by 74 publications

References 47 publications

RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins

RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins

ZFP36 RNA-binding proteins restrain T-cell activation and anti-viral immunity

Importance of the Conserved Carboxyl-Terminal CNOT1 Binding Domain to Tristetraprolin Activity In Vivo

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