William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Translational Science, Achilles Therapeutics Ltd, Stevenage Bioscience Catalyst, Stevenage, UK.
Nat Commun. 2021 Jun 7;12(1):3379. doi: 10.1038/s41467-021-23715-7.
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 PGC1α 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). PGC1α, 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 是一种谱系特异性转录因子，可驱动 CD4 T 辅助 2（Th2）细胞的分化，但也参与其他 T 细胞和非 T 细胞谱系中的多种过程，如免疫调节、增殖和维持。在这里，我们展示了 CD4 T 细胞利用的一种机制，通过 GATA3 和 AMPK 的作用，响应 DNA 损伤增加线粒体质量。激活的 AMPK 在转录水平上增加过氧化物酶体增殖物激活受体γ共激活因子 1α（PPARG 共激活因子 1α 或 PGC1α 蛋白）的表达，在翻译水平上增加 GATA3 的表达，而 DNA 损伤增强核因子红细胞 2 相关因子 2（NFE2L2 或 NRF2）的表达。PGC1α、GATA3 和 NRF2 与 ATR 一起复合物促进线粒体生物发生。这些发现扩展了 GATA3 的多效性相互作用，并强调了针对 GATA3 的细胞操作的潜力，以干预 DNA 损伤后 CD4 T 细胞的存活和功能。
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