1. Chromosomes and Gene Expression
  2. Immunology and Inflammation

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

  1. Michael J Moore
  2. Nathalie E Blachere
  3. John J Fak
  4. Christopher Y Park
  5. Kirsty Sawicka
  6. Salina Parveen
  7. Ilana Zucker-Scharff
  8. Bruno Moltedo
  9. Alexander Y Rudensky
  10. Robert B Darnell  Is a corresponding author
  1. The Rockefeller University, United States
  2. Memorial Sloan Kettering Cancer Center, United States
https://doi.org/10.7554/eLife.33057
Share this article
Cite this article
  1. Michael J Moore
  2. Nathalie E Blachere
  3. John J Fak
  4. Christopher Y Park
  5. Kirsty Sawicka
  6. Salina Parveen
  7. Ilana Zucker-Scharff
  8. Bruno Moltedo
  9. Alexander Y Rudensky
  10. Robert B Darnell
(2018)
ZFP36 RNA-binding proteins restrain T-cell activation and anti-viral immunity
eLife 7:e33057.
https://doi.org/10.7554/eLife.33057
  2. Download BibTeX
  3. Download .RIS

Abstract

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 mouse T cells, revealing 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 novel AU-rich sites in coding sequence. Functional studies revealed that ZFP36 regulates early T cell activation kinetics cell autonomously, 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 strategy to enhance immune-based therapies.

Data availability

Sequencing data are in GEO under the accession code GSE96076

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Michael J Moore

    Laboratory of Molecular Neuro-Onology, The Rockefeller University, New York, United States
    Competing interests
    Michael J Moore, currently affiliated with Regeneron Phrmaceuticals. The author has no other financial competing interests to declare.

  2. Nathalie E Blachere

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  3. John J Fak

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  4. Christopher Y Park

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  5. Kirsty Sawicka

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  6. Salina Parveen

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  7. Ilana Zucker-Scharff

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.

  8. Bruno Moltedo

    The Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.

  9. Alexander Y Rudensky

    The Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.

  10. Robert B Darnell

    Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
    For correspondence
    darnelr@rockefeller.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5134-8088

Funding

National Institutes of Health

  • Robert B Darnell

Starr Foundation

  • Robert B Darnell

Jane Coffin Childs Memorial Fund for Medical Research

  • Michael J Moore

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mouse strains were maintained at the University of California, San Francisco (UCSF) specific pathogen-free animal facility under protocol number AN110094. All animal protocols were approved by and in accordance with the guidelines established by the Institutional Animal Care and Use Committee and Laboratory Animal Resource Center

Copyright

© 2018, Moore et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 8,614
    views
  • 989
    downloads
  • 110
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Michael J Moore
  2. Nathalie E Blachere
  3. John J Fak
  4. Christopher Y Park
  5. Kirsty Sawicka
  6. Salina Parveen
  7. Ilana Zucker-Scharff
  8. Bruno Moltedo
  9. Alexander Y Rudensky
  10. Robert B Darnell
(2018)
ZFP36 RNA-binding proteins restrain T-cell activation and anti-viral immunity
eLife 7:e33057.
https://doi.org/10.7554/eLife.33057

Share this article

https://doi.org/10.7554/eLife.33057

Categories and tags

Research organism

Further reading

    1. Chromosomes and Gene Expression

    Nuclear Argonaute protein NRDE-3 switches small RNA partners during embryogenesis to mediate temporal-specific gene regulatory activity

    Shihui Chen, Carolyn Marie Phillips
    Research Article

    RNA interference (RNAi) is a conserved pathway that utilizes Argonaute proteins and their associated small RNAs to exert gene regulatory function on complementary transcripts. While the majority of germline-expressed RNAi proteins reside in perinuclear germ granules, it is unknown whether and how RNAi pathways are spatially organized in other cell types. Here, we find that the small RNA biogenesis machinery is spatially and temporally organized during Caenorhabditis elegans embryogenesis. Specifically, the RNAi factor, SIMR-1, forms visible concentrates during mid-embryogenesis that contain an RNA-dependent RNA polymerase, a poly-UG polymerase, and the unloaded nuclear Argonaute protein, NRDE-3. Curiously, coincident with the appearance of the SIMR granules, the small RNAs bound to NRDE-3 switch from predominantly CSR-class 22G-RNAs to ERGO-dependent 22G-RNAs. NRDE-3 binds ERGO-dependent 22G-RNAs in the somatic cells of larvae and adults to silence ERGO-target genes; here we further demonstrate that NRDE-3-bound, CSR-class 22G-RNAs repress transcription in oocytes. Thus, our study defines two separable roles for NRDE-3, targeting germline-expressed genes during oogenesis to promote global transcriptional repression, and switching during embryogenesis to repress recently duplicated genes and retrotransposons in somatic cells, highlighting the plasticity of Argonaute proteins and the need for more precise temporal characterization of Argonaute-small RNA interactions.

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics

    Transcription: The plusses and minuses of DNA torsion

    Steven Henikoff, David L Levens
    Insight

    A new method for mapping torsion provides insights into the ways that the genome responds to the torsion generated by RNA polymerase II.

    1. Cell Biology
    2. Chromosomes and Gene Expression

    The conserved ATPase PCH-2 controls the number and distribution of crossovers by antagonizing their formation in Caenorhabditis elegans

    Bhumil Patel, Maryke Grobler ... Needhi Bhalla
    Research Article

    Meiotic crossover recombination is essential for both accurate chromosome segregation and the generation of new haplotypes for natural selection to act upon. This requirement is known as crossover assurance and is one example of crossover control. While the conserved role of the ATPase, PCH-2, during meiotic prophase has been enigmatic, a universal phenotype when pch-2 or its orthologs are mutated is a change in the number and distribution of meiotic crossovers. Here, we show that PCH-2 controls the number and distribution of crossovers by antagonizing their formation. This antagonism produces different effects at different stages of meiotic prophase: early in meiotic prophase, PCH-2 prevents double-strand breaks from becoming crossover-eligible intermediates, limiting crossover formation at sites of initial double-strand break formation and homolog interactions. Later in meiotic prophase, PCH-2 winnows the number of crossover-eligible intermediates, contributing to the designation of crossovers and ultimately, crossover assurance. We also demonstrate that PCH-2 accomplishes this regulation through the meiotic HORMAD, HIM-3. Our data strongly support a model in which PCH-2’s conserved role is to remodel meiotic HORMADs throughout meiotic prophase to destabilize crossover-eligible precursors and coordinate meiotic recombination with synapsis, ensuring the progressive implementation of meiotic recombination and explaining its function in the pachytene checkpoint and crossover control.