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

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.

• Publication year

  2018

• Venue

  bioRxiv

• Publication date

  2018-01-14

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1101/247668PMID 29848443PMCID 6033538
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• RNA Binding

  2020cited by this paper
• Sequence Analysis

  2020cited by this paper
• The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation

  2016cited by this paper
• CLIP Tool Kit (CTK): a flexible and robust pipeline to analyze CLIP sequencing data

  2016cited by this paper
• The RNA-Binding Proteins Zfp36l1 and Zfp36l2 Enforce the Thymic β-Selection Checkpoint by Limiting DNA Damage Response Signaling and Cell Cycle Progression

  2016cited by this paper
• Tristetraprolin binding site atlas in the macrophage transcriptome reveals a switch for inflammation resolution

  2016cited by this paper
• Tristetraprolin as a Therapeutic Target in Inflammatory Disease.

  2016cited by this paper
• RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence

  2016cited by this paper
• Tristetraprolin Recruits Eukaryotic Initiation Factor 4E2 To Repress Translation of AU-Rich Element-Containing mRNAs

  2015influential reference
• Mapping Argonaute and conventional RNA-binding protein interactions with RNA at single-nucleotide resolution using HITS-CLIP and CIMS analysis

  2014influential reference
• Molecular and transcriptional basis of CD4⁺ T cell dysfunction during chronic infection.

  2014influential reference
• Post-transcriptional coordination of immunological responses by RNA-binding proteins

  2014cited by this paper
• HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism.

  2014cited by this paper
• HTSeq—a Python framework to work with high-throughput sequencing data

  2014cited by this paper
• Structural basis for the recruitment of the human CCR4–NOT deadenylase complex by Tristetraprolin

  2013cited by this paper
• Software for Computing and Annotating Genomic Ranges

  2013cited by this paper
• STAR: ultrafast universal RNA-seq aligner

  2013cited by this paper
• Dynamic regulatory network controlling Th17 cell differentiation

  2013cited by this paper
• 骨髄異形成症候群のgenome-wide analysis

  2013cited by this paper
• RNA decay mechanisms: specificity through diversity.

  2013cited by this paper
• Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action.

  2013cited by this paper
• Fast gapped-read alignment with Bowtie 2

  2012cited by this paper
• Tristetraprolin impairs myc-induced lymphoma and abolishes the malignant state.

  2012cited by this paper
• The p38/MK2-Driven Exchange between Tristetraprolin and HuR Regulates AU–Rich Element–Dependent Translation

  2012cited by this paper
• Myeloid-Specific Tristetraprolin Deficiency in Mice Results in Extreme Lipopolysaccharide Sensitivity in an Otherwise Minimal Phenotype

  2012cited by this paper
• Tristetraprolin down‐regulates IL‐17 through mRNA destabilization

  2012cited by this paper
• Turnover of AU‐rich‐containing mRNAs during stress: a matter of survival

  2011cited by this paper
• Regulatory T Cells

  2011influential reference
• Tristetraprolin-driven regulatory circuit controls quality and timing of mRNA decay in inflammation

  2011cited by this paper
• AU-Rich-Element-Dependent Translation Repression Requires the Cooperation of Tristetraprolin and RCK/P54

  2011cited by this paper
• Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities.

  2010cited by this paper
• Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia

  2010influential reference
• Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia (vol 11, pg 717, 2010)

  2010cited by this paper
• edgeR: a Bioconductor package for differential expression analysis of digital gene expression data

  2009cited by this paper
• Genome-Wide Analysis in Vivo of Translation with Nucleotide Resolution Using Ribosome Profiling

  2009cited by this paper
• The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules

  2009cited by this paper
• Tristetraprolin Mediates Interferon-γ mRNA Decay*

  2009cited by this paper
• Viral Sequestration of Antigen Subverts Cross Presentation to CD8+ T Cells

  2009cited by this paper
• HITS-CLIP yields genome-wide insights into brain alternative RNA processing

  2008cited by this paper
• Regulatory T Cells Dynamically Control the Primary Immune Response to Foreign Antigen1

  2007cited by this paper
• RNA-binding proteins.

  2006cited by this paper
• Tristetraprolin Down-Regulates IL-2 Gene Expression through AU-Rich Element-Mediated mRNA Decay1

  2005cited by this paper
• From the Cover: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

  2005cited by this paper
• Recruitment and activation of mRNA decay enzymes by two ARE-mediated decay activation domains in the proteins TTP and BRF-1.

  2005influential reference
• Analysis of a noncanonical poly(A) site reveals a tripartite mechanism for vertebrate poly(A) site recognition.

  2005cited by this paper
• Java Treeview - extensible visualization of microarray data

  2004cited by this paper
• RNA Sequence Elements Required for High Affinity Binding by the Zinc Finger Domain of Tristetraprolin

  2004cited by this paper
• Open source clustering software.

  2004cited by this paper
• Expression, purification, and biochemical characterization of the antiinflammatory tristetraprolin: a zinc-dependent mRNA binding protein affected by posttranslational modifications.

  2004cited by this paper
• Expression and purification of recombinant tristetraprolin that can bind to tumor necrosis factor-alpha mRNA and serve as a substrate for mitogen-activated protein kinases.

  2003cited by this paper
• Immunoaffinity purification of mammalian protein complexes.

  2003cited by this paper
• CLIP Identifies Nova-Regulated RNA Networks in the Brain

  2003cited by this paper
• RNA Binding Properties of the AU-rich Element-binding Recombinant Nup475/TIS11/Tristetraprolin Protein*

  2002cited by this paper
• HuA and Tristetraprolin Are Induced following T Cell Activation and Display Distinct but Overlapping RNA Binding Specificities*

  2001cited by this paper
• Tristetraprolin and other CCCH tandem zinc-finger proteins in the regulation of mRNA turnover.

  2001cited by this paper
• Feedback Inhibition of Macrophage Tumor Necrosis Factor-α Production by Tristetraprolin

  1998cited by this paper
• Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin.

  1998influential reference
• A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency.

  1996cited by this paper
• Promoter Analysis of Zfp-36, the Mitogen-inducible Gene Encoding the Zinc Finger Protein Tristetraprolin (*)

  1995cited by this paper
• CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection

  1994cited by this paper
• Selective degradation of early-response-gene mRNAs: functional analyses of sequence features of the AU-rich elements

  1994cited by this paper
• Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor

  1992cited by this paper
• A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation.

  1986cited by this paper
• Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators.

  1986cited by this paper
• Genomic and biological variation among commonly used lymphocytic choriomeningitis virus strains.

  1983cited by this paper
• Gene set enrichment analysis: a knowledge-based approach for interpreting

  year unknowncited by this paper

• Expression and role of the RNA-binding protein, ZFP36L1, in mouse T follicular helper cell differentiation and function

  2026cites this paper
• RNA-binding proteins and ribonucleoproteins as determinants of immunity.

  2026cites this paper
• Expansion of Interleukin‐22‐Producing Type 3 Innate Lymphoid Cells in the Gut of Tristetraprolin‐Deficient Mice

  2025cites this paper
• ScRNA-Seq reveals T cell immunity in COVID-19 patients and implications for immunotherapy.

  2025cites this paper
• ZFP36-family RNA-binding proteins in regulatory T cells reinforce immune homeostasis

  2025influential citation
• Restoration of LAT activity improves CAR T cell sensitivity and persistence in response to antigen-low acute lymphoblastic leukemia.

  2025cites this paper
• Terminal differentiation and persistence of effector regulatory T cells essential for preventing intestinal inflammation

  2025cites this paper
• Durable response to CAR T is associated with elevated activation and clonotypic expansion of the cytotoxic native T cell repertoire

  2025influential citation
• Multimodal delineation of a layer of effector function among exhausted CD8 T cells in tumors.

  2025cites this paper
• Respiratory viral infections awaken metastatic breast cancer cells in lungs

  2025cites this paper
• ZFP36L1 and L2 as novel antiviral factors for Crimean-Congo hemorrhagic fever virus via interaction with viral nucleoprotein

  2025cites this paper
• Regulation of mRNA metabolism in immune cells

  2025cites this paper
• Single-cell RNA transcriptome analysis reveals regulatory programs of RNA binding proteins in diabetic foot ulcers

  2025cites this paper
• Decoding the association between mucosal-associated invariant T cells and prostate cancer via multi-omics analysis

  2025cites this paper
• TEAMwork: Interplay of Post‐Transcriptional Mechanisms, Epigenetics and Metabolism in (Auto‐)Immunity

  2025cites this paper
• Differential Regulation of TCR‐Induced ZFP36 and ZFP36L1 Expression by Cyclosporin A in CD8+ T Cells

  2025cites this paper
• The ZFP36-FTO axis is a key regulator of macrophage activation and a druggable therapeutic target of sepsis

  2025cites this paper
• Single-cell profiling reveals a reduced epithelial defense system, decreased immune responses and the immune regulatory roles of different fibroblast subpopulations in chronic atrophic gastritis

  2025cites this paper
• Inherent Specificity and Mutational Sensitivity as Quantitative Metrics for RBP Binding

  2025cites this paper
• Stepwise single-cell data identifies RNA binding proteins associated with the development of head and neck cancer and tumor microenvironment remodeling

  2025cites this paper
• A novel ferroptosis-related gene signature for overall survival prediction in patients with gastric cancer

  2024cites this paper
• ZFP36, an RNA-binding protein promotes hBMSCs osteogenic differentiation via binding with JUN

  2024cites this paper
• Single‐cell characterization of differentiation trajectories and drug resistance features in gastric cancer with peritoneal metastasis

  2024cites this paper
• Zinc pathogenic importance in correcting immunity and restoring public health in the post-COVID period: An overview.

  2024cites this paper
• A novel metric-based approach of scoring early host immune response from oro-nasopharyngeal swabs predicts COVID-19 outcome

  2024cites this paper
• Opto-CLIP reveals dynamic FMRP regulation of mRNAs upon CA1 neuronal activation

  2024cites this paper
• LIM-domain-only 4 (LMO4) enhances CD8+ T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling

  2024cites this paper
• Regulation of IFN‐γ production by ZFP36L2 in T cells is time‐dependent

  2024cites this paper
• Mapping spatially resolved transcriptomes in human and mouse pulmonary fibrosis

  2024cites this paper
• Multiple roles for AU-rich RNA binding proteins in the development of haematologic malignancies and their resistance to chemotherapy

  2024cites this paper
• The aged tumor microenvironment limits T cell control of cancer

  2024cites this paper
• Mapping RNA–protein interactions with subcellular resolution using colocalization CLIP

  2024cites this paper
• Respiratory viral infection promotes the awakening and outgrowth of dormant metastatic breast cancer cells in lungs

  2024cites this paper
• Turnover of PPP1R15A mRNA encoding GADD34 controls responsiveness and adaptation to cellular stress.

  2024cites this paper
• Exploration of signature based on T cell-related genes in stomach adenocarcinoma by analysis of single cell sequencing data

  2024cites this paper
• Inflammation as a driver of hematological malignancies

  2024cites this paper
• Targeting pro-inflammatory T cells as a novel therapeutic approach to potentially resolve atherosclerosis in humans

  2024cites this paper
• ZFP36 disruption is insufficient to enhance the function of mesothelin-targeting human CAR-T cells

  2024influential citation
• Tumor reactive γδ T cells contribute to a complete response to PD-1 blockade in a Merkel cell carcinoma patient

  2024cites this paper
• Ribosome profiling: a powerful tool in oncological research

  2024cites this paper
• Defining cell type-specific immune responses in a mouse model of allergic contact dermatitis by single-cell transcriptomics

  2024cites this paper
• Combined Deletion of ZFP36L1 and ZFP36L2 Drives Superior Cytokine Production in T Cells at the Cost of Cell Fitness

  2024cites this paper
• Tristetraprolin-mediated mRNA destabilization regulates basophil inflammatory responses.

  2024cites this paper
• Mapping RNA-Protein Interactions with Subcellular Resolution Using Colocalization CLIP

  2023cites this paper
• Bioinformatics-led discovery of ferroptosis-associated diagnostic biomarkers and molecule subtypes for tuberculosis patients

  2023cites this paper
• Multimodal delineation of a layer of effector function among exhausted CD8 T cells in tumors

  2023cites this paper
• Early-to-mid stage idiopathic Parkinson’s disease shows enhanced cytotoxicity and differentiation in CD8 T-cells in females

  2023cites this paper
• Identification of A Novel Gene Signature Combining Ferroptosis- and Immunity-Related Genes for Prognostic Prediction, Immunotherapy and Potential Therapeutic Targets in Gastric Cancer

  2023cites this paper
• Endothelial Jagged1 levels and distribution are post-transcriptionally controlled by ZFP36 decay proteins

  2023cites this paper
• Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity

  2023cites this paper
• The RNA‐binding protein ZFP36 strengthens innate antiviral signaling by targeting RIG‐I for K63‐linked ubiquitination

  2023cites this paper
• Post-transcriptional checkpoints in autoimmunity

  2023cites this paper
• Proteogenomic and V(D)J Analysis of Human Decidual T Cells Highlights Unique Transcriptional Programming and Clonal Distribution.

  2023cites this paper
• Zfp36l1 establishes the high‐affinity CD8 T‐cell response by directly linking TCR affinity to cytokine sensing

  2023cites this paper
• The role of eIF4F-driven mRNA translation in regulating the tumour microenvironment

  2023cites this paper
• ZFP36-mediated mRNA decay regulates metabolism

  2023cites this paper
• Regulation and function of poised mRNAs in lymphocytes

  2023cites this paper
• Integrative multi-omics approaches to explore immune cell functions: Challenges and opportunities.

  2023cites this paper
• Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation

  2023cites this paper
• Type I IFN stimulates lymph node stromal cells from adult and old mice during a West Nile virus infection

  2023cites this paper
• Correlated evolution of social organization and lifespan in mammals

  2023cites this paper
• A Distinct Phenotype of Polarized Memory B cell holds IgE Memory

  2023cites this paper
• RNA circuits and RNA-binding proteins in T cells.

  2023cites this paper
• Construction and validation of a novel ferroptosis-related signature for evaluating prognosis and immune microenvironment in ovarian cancer

  2023cites this paper
• The ZFP36 family of RNA binding proteins regulates homeostatic and autoreactive T cell responses

  2022influential citation
• Translation and emerging functions of non‐coding RNAs in inflammation and immunity

  2022cites this paper
• Tfh-cell-derived interleukin 21 sustains effector CD8+ T cell responses during chronic viral infection.

  2022cites this paper
• In heart failure reactivation of RNA-binding proteins is associated with the expression of 1,523 fetal-specific isoforms

  2022cites this paper
• Deciphering the Molecular Signature of Human Hyalocytes in Relation to Other Innate Immune Cell Populations

  2022cites this paper
• Distinct mechanisms of mismatch repair deficiency delineate two modes of response to PD-1 immunotherapy in endometrial carcinoma.

  2022cites this paper
• Interactome of SARS-CoV-2 Modulated Host Proteins With Computationally Predicted PPIs: Insights From Translational Systems Biology Studies

  2022cites this paper
• Dynamic and widespread control of poly(A) tail length during macrophage activation

  2022cites this paper
• Beta-hydroxybutyrate dampens adipose progenitors’ profibrotic activation through canonical Tgfβ signaling and non-canonical ZFP36-dependent mechanisms

  2022cites this paper
• A novel peptide protects against diet-induced obesity by suppressing appetite and modulating the gut microbiota

  2022cites this paper
• Keeping development on time: Insights into post‐transcriptional mechanisms driving oscillatory gene expression during vertebrate segmentation

  2022cites this paper
• Identification of COVID-19-Specific Immune Markers Using a Machine Learning Method

  2022cites this paper
• Sexually dimorphic transcriptional programs of early-phase response in regenerating peripheral nerves

  2022cites this paper
• A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity

  2022cites this paper
• HUWE1 controls tristetraprolin proteasomal degradation by regulating its phosphorylation

  2022cites this paper
• The druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease

  2022cites this paper
• A Novel Prognosis Signature Based on Ferroptosis-Related Gene DNA Methylation Data for Lung Squamous Cell Carcinoma

  2022cites this paper
• ADAR2 deaminase activity promotes Th17 effector function and protects against intestine inflammation

  2022cites this paper
• TiO2 nanoparticles abrogate the protective effect of the Crohn’s disease-associated variation within the PTPN22 gene locus

  2022cites this paper
• Heterogeneity and Differentiation Trajectories of Infiltrating CD8+ T Cells in Lung Adenocarcinoma

  2022cites this paper
• RNA Metabolism in T Lymphocytes

  2022cites this paper
• Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell

  2022cites this paper
• AGO HITS-CLIP reveals distinct miRNA regulation of white and brown adipose tissue identity

  2021cites this paper
• Integrated analysis of RNA-binding proteins in thyroid cancer

  2021cites this paper
• Control of RNA Stability in Immunity.

  2021cites this paper
• Immune features of COVID-19 convalescent individuals revealed by a single-cell RNA sequencing

  2021cites this paper
• ImmReg: the regulon atlas of immune-related pathways across cancer types

  2021cites this paper
• Time-dependent regulation of cytokine production by RNA binding proteins defines T cell effector function

  2021cites this paper
• Surface antigen-guided CRISPR screens identify regulators of myeloid leukemia differentiation.

  2021cites this paper
• Conceptual Advances in Control of Inflammation by the RNA-Binding Protein Tristetraprolin

  2021influential citation
• Single cell multi-omics reveals early elevated function and multiple fates within human progenitor exhausted CD8+ T cells

  2021cites this paper
• Sequence determinants as key regulators in gene expression of T cells

  2021cites this paper
• Tristetraprolin Gene Single-Nucleotide Polymorphisms and mRNA Level in Patients With Rheumatoid Arthritis

  2021cites this paper
• Defining the RBPome of primary T helper cells to elucidate higher-order Roquin-mediated mRNA regulation

  2021cites this paper
• RNA-Binding Motif Protein 11 (RBM11) Serves as a Prognostic Biomarker and Promotes Ovarian Cancer Progression

  2021cites this paper
• Multiomic analysis reveals decidual‐specific transcriptional programing of MAIT cells

  2021cites this paper