The thioredoxin-1 system is essential for fueling DNA synthesis during T-cell metabolic reprogramming and proliferation

Nature Communications
Jonathan MuriManfred Kopf

Abstract

The thioredoxin-1 (Trx1) system is an important contributor to cellular redox balance and is a sensor of energy and glucose metabolism. Here we show critical c-Myc-dependent activation of the Trx1 system during thymocyte and peripheral T-cell proliferation, but repression during T-cell quiescence. Deletion of thioredoxin reductase-1 (Txnrd1) prevents expansion the CD4-CD8- thymocyte population, whereas Txnrd1 deletion in CD4+CD8+ thymocytes does not affect further maturation and peripheral homeostasis of αβT cells. However, Txnrd1 is critical for expansion of the activated T-cell population during viral and parasite infection. Metabolomics show that TrxR1 is essential for the last step of nucleotide biosynthesis by donating reducing equivalents to ribonucleotide reductase. Impaired availability of 2'-deoxyribonucleotides induces the DNA damage response and cell cycle arrest of Txnrd1-deficient T cells. These results uncover a pivotal function of the Trx1 system in metabolic reprogramming of thymic and peripheral T cells and provide a rationale for targeting Txnrd1 in T-cell leukemia.

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Citations

Jun 12, 2019·BioFactors·José Luis García-GiménezFederico V Pallardó
Sep 10, 2020·European Journal of Immunology·Jonathan MuriManfred Kopf
Nov 16, 2018·Cellular and Molecular Life Sciences : CMLS·Luiz Gustavo de Almeida ChuffaLuiz Antonio Lupi
Apr 12, 2019·The Journal of Biological Chemistry·Paramita ChakrabortyShikhar Mehrotra
Jun 13, 2020·Frontiers in Cell and Developmental Biology·Li ZhouQing-Sheng Mi
May 13, 2019·Cancer Chemotherapy and Pharmacology·Jin-Jing JiaXian-Si Zeng
Jan 19, 2021·Free Radical Biology & Medicine·Fang-Yi SuWen-Hwa Lee
Jan 24, 2021·NPJ Systems Biology and Applications·Bhanwar Lal PuniyaTomáš Helikar
Dec 20, 2020·Nature Reviews. Immunology·Jonathan Muri, Manfred Kopf
Jan 26, 2021·Clinical Science·Rui ZhouJingjing Zhang
Feb 18, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Paul D KruithofHarry van Goor
Nov 21, 2020·Seminars in Cell & Developmental Biology·Chi Ma, Peter R Hoffmann
Sep 30, 2020·Redox Biology·Jinsong ZhangMargaret P Rayman
May 14, 2021·Nature Reviews. Immunology·Miguel Reina-CamposAnanda W Goldrath
Aug 20, 2021·American Journal of Reproductive Immunology : AJRI·Jessica VazquezAleksandar K Stanic
Aug 28, 2021·Annual Review of Pharmacology and Toxicology·Radosveta Gencheva, Elias S J Arnér

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Datasets Mentioned

BETA
GSE107090

Methods Mentioned

BETA
flow cytometry
FACS
RNA-seq
PCR
RNAseq
FCS
Assay
Protein Assay

Software Mentioned

STAR aligner
Bioconductor
edgeR

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