Survivin promotes a glycolytic switch in CD4+ T cells by suppressing the transcription of PFKFB3 in rheumatoid arthritis
Malin C. Erlandsson,
Karin M.E. Andersson,
Nina Y. Oparina,
Venkataragavan Chandrasekaran,
Tibor Saghy,
Anastasios Damdimopoulos,
Maria-Jose Garcia-Bonete,
Zakaria Einbeigi,
Sofia T. Silfverswärd,
Marcela Pekna,
Gergely Katona,
Maria I. Bokarewa
Affiliations
Malin C. Erlandsson
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530 Gothenburg, Sweden; Rheumatology Clinic, Sahlgrenska University Hospital, Gröna stråket 16, 41346 Gothenburg, Sweden
Karin M.E. Andersson
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530 Gothenburg, Sweden
Nina Y. Oparina
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530 Gothenburg, Sweden
Venkataragavan Chandrasekaran
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530 Gothenburg, Sweden
Tibor Saghy
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530 Gothenburg, Sweden
Anastasios Damdimopoulos
Bioinformatics and Expression Analysis Core Facility, Department of Biosciences and Nutrition, Karolinska Institute, 141 41 Huddinge, Sweden
Maria-Jose Garcia-Bonete
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, 40530 Gothenburg, Sweden
Zakaria Einbeigi
Department of Medicine and Oncology, Southern Älvsborg Hospital, 50182 Borås, Sweden; Department of Oncology, Institute of Clinical Science at Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
Sofia T. Silfverswärd
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530 Gothenburg, Sweden
Marcela Pekna
Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Box 440, 40530 Gothenburg, Sweden
Gergely Katona
Department of Chemistry and Molecular Biology, Faculty of Science, University of Gothenburg, 405 30 Gothenburg, Sweden
Maria I. Bokarewa
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Box 480, 40530 Gothenburg, Sweden; Rheumatology Clinic, Sahlgrenska University Hospital, Gröna stråket 16, 41346 Gothenburg, Sweden; Corresponding author
Summary: 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.
