期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-23715-7
关键词
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资金
- British Heart Foundation [FS/15/69/32043]
- Springboard award from the Academy of Medical Science
- Wellcome trust [SBF001\1013]
- Rosetrees Trust [M731]
- Barts and the London Charity [MGU0536]
- Royal College of Anaesthetists [WRO-2018-0065]
- Asthma UK
- BRC at Guy's and St.Thomas' Hospitals
- Barts and the London Charity grant [MGU0293]
- CRUK Flow Cytometry Core Service at Barts Cancer Institute [C16420/A18066]
- Medical Research Council [MR/P00184X/1]
This study investigates the role of GATA3 in regulating mitochondrial mass and biogenesis in CD4(+) T cells in response to DNA damage, through the actions of AMPK. The findings expand the understanding of the pleiotropic interactions of GATA3 and suggest the potential for GATA3-targeted interventions in CD4(+) T cell viability and function after DNA damage.
GATA3 is as a lineage-specific transcription factor that drives the differentiation of CD4(+) T helper 2 (Th2) cells, but is also involved in a variety of processes such as immune regulation, proliferation and maintenance in other T cell and non-T cell lineages. Here we show a mechanism utilised by CD4(+) T cells to increase mitochondrial mass in response to DNA damage through the actions of GATA3 and AMPK. Activated AMPK increases expression of PPARG coactivator 1 alpha (PPARGC1A or PGC1 alpha protein) at the level of transcription and GATA3 at the level of translation, while DNA damage enhances expression of nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). PGC1 alpha, GATA3 and NRF2 complex together with the ATR to promote mitochondrial biogenesis. These findings extend the pleotropic interactions of GATA3 and highlight the potential for GATA3-targeted cell manipulation for intervention in CD4(+) T cell viability and function after DNA damage. GATA3 has been considered to be primarily associated with CD4(+) Th2 cell function. Using CD4(+) effector memory that re-express CD45RA (EMRA) T cells the authors show that in response to DNA damage GATA3 can regulate increase of mitochondrial mass and biogenesis involving AMPK.
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