Chromatin binding of survivin regulates glucose metabolism in the IFN-g producing CD4+T cells
Erlandsson, M. C.; Andersson, K. M.; Oparina, N. Y.; Chandrasekaran, V.; Damdimopoulos, A.; Garcia-Bonete, M.-J.; Einbeigi, Z.; Silfversward, S. T.; Pekna, M. C.; Katona, G. C.; Bokarewa, M. I.
Show abstract
Interferon-gamma (IFN{gamma}) producing T cells develop metabolic adaptation required for their effector functions in tumour biology, autoimmunity and antiviral defence. Using sorted CD4+ cells we demonstrated that glycolytic switch and high glucose uptake in IFN{gamma}-producing cells was associated with survivin expression. Inhibition of survivin restored glycolysis by upregulating the transcription of phosphofructokinase PFKFB3 and reducing glucose uptake. Integration of the whole-genome sequencing of the chromatin immunoprecipitated with survivin with transcription changes in CD4+ cells after survivin inhibition revealed co-localization of survivin, IRF1 and SMAD3 in the regulatory elements paired to the differentially expressed genes. Western blot demonstrated direct binding of survivin to IRF1 and SMAD3. Functionally, inhibition of survivin repressed IFN{gamma} signalling and activated SMAD3-dependent protein remodelling, which resulted in the effector-to-memory transition of CD4+ cells. These findings demonstrate the key role of survivin in IFN{gamma}-dependent metabolic adaptation and identify survivin inhibition as an attractive strategy to counteract these effects.
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