Abstract
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.
Original language | English |
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Article number | 19657 |
Number of pages | 24 |
Journal | Scientific Reports |
Volume | 12 |
Issue number | 1 |
DOIs | |
Publication status | Published - 16 Nov 2022 |
Bibliographical note
Funding:This work was funded by the Biotechnology and Biological Sciences Research Council grants BBS/E/B/000C0427 and BBS/E/B/000C0428, and a Wellcome Investigator award (200823/Z/16/Z) to M.T..
Copyright:
© 2022. The Author(s).
Keywords
- RNA, Messenger/genetics
- Glutamine
- Ketoglutaric Acids
- T-Lymphocytes/metabolism
- CD4-Positive T-Lymphocytes/metabolism