Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-24132-6 |
| _version_ | 1811309243965374464 |
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| author | Louise S. Matheson Georg Petkau Beatriz Sáenz-Narciso Vanessa D’Angeli Jessica McHugh Rebecca Newman Haydn Munford James West Krishnendu Chakraborty Jennie Roberts Sebastian Łukasiak Manuel D. Díaz-Muñoz Sarah E. Bell Sarah Dimeloe Martin Turner |
| author_facet | Louise S. Matheson Georg Petkau Beatriz Sáenz-Narciso Vanessa D’Angeli Jessica McHugh Rebecca Newman Haydn Munford James West Krishnendu Chakraborty Jennie Roberts Sebastian Łukasiak Manuel D. Díaz-Muñoz Sarah E. Bell Sarah Dimeloe Martin Turner |
| author_sort | Louise S. Matheson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T09:38:47Z |
| format | Article |
| id | doaj.art-502be5987af14790b105142b3363eb12 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-13T09:38:47Z |
| publishDate | 2022-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-502be5987af14790b105142b3363eb122022-12-22T02:52:00ZengNature PortfolioScientific Reports2045-23222022-11-0112112410.1038/s41598-022-24132-6Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cellLouise S. Matheson0Georg Petkau1Beatriz Sáenz-Narciso2Vanessa D’Angeli3Jessica McHugh4Rebecca Newman5Haydn Munford6James West7Krishnendu Chakraborty8Jennie Roberts9Sebastian Łukasiak10Manuel D. Díaz-Muñoz11Sarah E. Bell12Sarah Dimeloe13Martin Turner14Immunology Programme, The Babraham Institute, Babraham Research CampusImmunology Programme, The Babraham Institute, Babraham Research CampusImmunology Programme, The Babraham Institute, Babraham Research CampusImmunology Programme, The Babraham Institute, Babraham Research CampusImmunology Programme, The Babraham Institute, Babraham Research CampusImmunology Programme, The Babraham Institute, Babraham Research CampusInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, IBR, University of BirminghamCambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of CambridgeImmunology Programme, The Babraham Institute, Babraham Research CampusInstitute of Metabolism and Systems Research, University of BirminghamImmunology Programme, The Babraham Institute, Babraham Research CampusImmunology Programme, The Babraham Institute, Babraham Research CampusImmunology Programme, The Babraham Institute, Babraham Research CampusInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, IBR, University of BirminghamImmunology Programme, The Babraham Institute, Babraham Research CampusAbstract 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.https://doi.org/10.1038/s41598-022-24132-6 |
| spellingShingle | Louise S. Matheson Georg Petkau Beatriz Sáenz-Narciso Vanessa D’Angeli Jessica McHugh Rebecca Newman Haydn Munford James West Krishnendu Chakraborty Jennie Roberts Sebastian Łukasiak Manuel D. Díaz-Muñoz Sarah E. Bell Sarah Dimeloe Martin Turner Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell Scientific Reports |
| title | Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell |
| title_full | Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell |
| title_fullStr | Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell |
| title_full_unstemmed | Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell |
| title_short | Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell |
| title_sort | multiomics analysis couples mrna turnover and translational control of glutamine metabolism to the differentiation of the activated cd4 t cell |
| url | https://doi.org/10.1038/s41598-022-24132-6 |
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