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ZFP36-family RNA-binding proteins in regulatory T cells reinforce immune homeostasis [bulk RNA-seq]

ABSTRACT: RNA binding proteins (RBP) of the ZFP36 family limit the differentiation and effector functions of CD4 and CD8 T cells, but little is known of their expression or function in regulatory T cells (Treg). By Treg-restricted deletion of Zfp36 family members we identify the essential role of Zfp36l1 and Zfp36l2 in Treg to maintain immune homeostasis. Mice with Tregs deficient in these RBP display an inflammatory phenotype with an expansion in the numbers of type-2 conventional dendritic cells, T effector cells, T follicular helper and germinal center B cells and elevated serum cytokines and immunoglobulins. In the absence of Zfp36l1 and Zfp36l2, the pool of cycling CTLA-4 in naïve Treg was reduced, Tregs were less sensitive to IL-2 and IL-7 but were more sensitive to IFNγ. In mice lacking both RBP in Treg, the deletion of a single allele of Ifng is sufficient to ameliorate the pathology. Thus, ZFP36L1 and ZFP36L2 regulate multiple pathways that enable Tregs to enforce immune homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE244619 | GEO | 2024/08/08

REPOSITORIES: GEO

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ZFP36-family RNA-binding proteins in regulatory T cells reinforce immune homeostasis [single cell RNA-seq]

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RNA-binding Protein ZFP36L2 Downregulates Helios Expression and Suppresses the Function of Regulatory T Cells

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The effect of ZFP36L1 deficiency on gene expression in the U2OS osteosarcoma cancer cell line

Project description:Post-transcriptional regulation of gene expression by RNA binding proteins (RBPs), one of the major classes of proteins encoded by the human genome, is well established. ZFP36L1 and its protein family members, ZFP36 and ZFP36L2, function as RBPs that primarily regulate gene expression at the post-transcriptional level by binding to adenine uridine (AU) rich elements (AREs) in the 3′ untranslated region (3′UTR) of certain mRNAs and mediating ARE-dependent mRNA decay. In this study, using CRISPR/Cas9 ZFP36L1 gene-editing, we generated ZFP36L1 deficient U2OS cellular models. The aim of the RNASeq experiment was to compare the gene expression profile in wild-type U2OS cells compared to ZFP36L1 deficient U2OS cells. Loss of functional ZFP36L1 leads to widespread changes in gene expression that are associated with dysregulation of KRAS signalling.

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Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell

Project description:The ZFP36 family of RNA-binding proteins acts post-transcriptionally to repress translation and promote RNA decay. Studies of genes and pathways regulated by the ZFP36 family in CD4+ T cells have focussed largely on cytokines, but their impact on metabolic reprogramming and differentiation is unclear. Using CD4+ T cells lacking Zfp36 and Zfp36l1, we combined the quantification of mRNA transcription, stability, abundance and translation with crosslinking immunoprecipitation and metabolic profiling to determine how they regulate T cell metabolism and differentiation. Our results suggest that ZFP36 and ZFP36L1 act directly to limit the expression of genes driving anabolic processes by two distinct routes: by targeting transcription factors and by targeting transcripts encoding rate-limiting enzymes. These enzymes span numerous metabolic pathways including glycolysis, one-carbon metabolism and glutaminolysis. Direct binding and repression of transcripts encoding glutamine transporter SLC38A2 correlated with increased cellular glutamine content in ZFP36/ZFP36L1-deficient T cells. Increased conversion of glutamine to α-ketoglutarate in these cells was consistent with direct binding of ZFP36/ZFP36L1 to Gls (encoding glutaminase) and Glud1 (encoding glutamate dehydrogenase). We propose that ZFP36 and ZFP36L1 as well as glutamine and α-ketoglutarate are limiting factors for the acquisition of the cytotoxic CD4+ T cell fate. Our data implicate ZFP36 and ZFP36L1 in limiting glutamine anaplerosis and differentiation of activated CD4+ T cells, likely mediated by direct binding to transcripts of critical genes that drive these processes.

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