Dataset Information

Survivin promotes a glycolytic switch in CD4⁺ T cells by suppressing the transcription of PFKFB3 in rheumatoid arthritis.

ABSTRACT: In this study, we explore the role of nuclear survivin in maintaining the effector phenotype of IFNγ-producing T cells acting through the transcriptional control of glucose utilization. High expression of survivin in CD4⁺T cells was associated with IFNγ-dependent phenotype and anaerobic glycolysis. Transcriptome of CD4⁺ cells and sequencing of survivin-bound chromatin showed that nuclear survivin had a genome-wide and motif-specific binding to regulatory regions of the genes controlling cell metabolism. Survivin coprecipitates with transcription factors IRF1 and SMAD3, which repressed the transcription of the metabolic check-point enzyme phosphofructokinase 2 gene PFKFB3 and promoted anaerobic glycolysis. Combining transcriptome analyses of CD4⁺ cells and functional studies in glucose metabolism, we demonstrated that the inhibition of survivin reverted PFKFB3 production, inhibited glucose uptake, and reduces interferon effects in CD4⁺ cells. These results present a survivin-dependent mechanism in coordinating the metabolic adaptation of CD4⁺T cells and propose an attractive strategy to counteract IFNγ-dependent inflammation in autoimmunity.

SUBMITTER: Erlandsson MC

PROVIDER: S-EPMC9678772 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Survivin promotes a glycolytic switch in CD4+ T cells by suppressing the transcription of PFKFB3 in rheumatoid arthritis.

Erlandsson Malin C MC Andersson Karin M E KME Oparina Nina Y NY Chandrasekaran Venkataragavan V Saghy Tibor T Damdimopoulos Anastasios A Garcia-Bonete Maria-Jose MJ Einbeigi Zakaria Z Silfverswärd Sofia T ST Pekna Marcela M Katona Gergely G Bokarewa Maria I MI

iScience 20221107 12

In this study, we explore the role of nuclear survivin in maintaining the effector phenotype of IFNγ-producing T cells acting through the transcriptional control of glucose utilization. High expression of survivin in CD4+T cells was associated with IFNγ-dependent phenotype and anaerobic glycolysis. Transcriptome of CD4+ cells and sequencing of survivin-bound chromatin showed that nuclear survivin had a genome-wide and motif-specific binding to regulatory regions of the gene ...[more]

PMID: 36425763

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Project description:BackgroundThe genetic risk associated with rheumatoid arthritis (RA) includes genes regulating DNA methylation, one of the hallmarks of epigenetic re-programing, as well as many T-cell genes, with a strong MHC association, pointing to immunogenetic mechanisms as disease triggers leading to chronicity. The aim of our study was to explore DNA methylation in early, drug-naïve RA patients, towards a better understanding of early events in pathogenesis.ResultMonocytes, naïve and memory CD4+ T-cells were sorted from 6 healthy controls and 10 RA patients. DNA methylation was assessed using a genome-wide Illumina 450K CpG promoter array. Differential methylation was confirmed using bisulfite sequencing for a specific gene promoter, ELISA for several cytokines and flow cytometry for cell surface markers. Differentially methylated (DM) CpGs were observed in 1047 genes in naïve CD4+ T-cells, 913 in memory cells and was minimal in monocytes with only 177 genes. Naive CD4+ T-cells were further investigated as presenting differential methylation in the promoter of > 500 genes associated with several disease-relevant pathways, including many cytokines and their receptors. We confirmed hypomethylation of a region of the TNF-alpha gene in early RA and differential expression of 3 cytokines (IL21, IL34 and RANKL). Using a bioinformatics package (DMRcate) and an in-house analysis based on differences in β values, we established lists of DM genes between health and RA. Publicly available gene expression data were interrogated to confirm differential expression of over 70 DM genes. The lists of DM genes were further investigated based on a functional relationship database analysis, which pointed to an IL6/JAK1/STAT3 node, related to TNF-signalling and engagement in Th17 cell differentiation amongst many pathways. Five DM genes for cell surface markers (CD4, IL6R, IL2RA/CD25, CD62L, CXCR4) were investigated towards identifying subpopulations of CD4+ T-cells undergoing these modifications and pointed to a subset of naïve T-cells, with high levels of CD4, IL2R, and CXCR4, but reduction and loss of IL6R and CD62L, respectively.ConclusionOur data provided novel conceptual advances in the understanding of early RA pathogenesis, with implications for early treatment and prevention.

Dataset Information

Survivin promotes a glycolytic switch in CD4⁺ T cells by suppressing the transcription of PFKFB3 in rheumatoid arthritis.

Publications

Survivin promotes a glycolytic switch in CD4<sup>+</sup> T cells by suppressing the transcription of PFKFB3 in rheumatoid arthritis.

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