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

ELife
Michael J MooreRobert B Darnell

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.

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Citations

Mar 1, 2020·European Journal of Immunology·Julian J Freen-van HeerenMonika C Wolkers
Sep 13, 2019·Journal of Biochemistry·Yutaro UchidaHiroshi Asahara
Aug 27, 2019·Immunological Medicine·Masanori Yoshinaga, Osamu Takeuchi
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Aug 20, 2021·American Journal of Reproductive Immunology : AJRI·Jessica VazquezAleksandar K Stanic
Nov 11, 2021·Nucleic Acids Research·Tiantongfei JiangXia Li

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Datasets Mentioned

BETA
GSE96076

Methods Mentioned

BETA
immunoprecipitation
HITS-CLIP
CLIP
RNAseq
flow cytometry
transgenic
iCLIP
ELISA
transfection
PCR

Software Mentioned

TopGO
edgeR
custom R scripts
GSEA
Cluster
Bowtie
Gene Set Enrichment Analysis ( GSEA )
HOMER
Treeview
STAR

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