Abstract
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.
Highlights
GATA binding protein 3 (GATA3) is as a lineage-specific transcription factor that drives the differentiation of CD4+ T helper 2 (Th2) cells, but is involved in a variety of processes such as immune regulation, proliferation and maintenance in other T cell and non-T cell lineages
PGC1α and GATA3 form a complex with the Serine/threonineprotein kinase ATR (ATR) and nuclear factor erythroid 2-related factor 2 (NRF2) to enhance mitochondrial biogenesis to maintain the viability of CD4+ T cells during DNA damage
We examined the expression of GATA3 in primary human CD4+ T cell subsets defined by CD45RA and CD27 expression (Supplementary Fig. 1a)—Naive (CD45RA+CD27+), central memory (CM; CD45RA−CD27+), effector memory (EM; CD45RA−CD27−) and effector memory that re-express CD45RA (EMRA; CD45RA+CD27−)[10,11]
Summary
GATA3 is as a lineage-specific transcription factor that drives the differentiation of CD4+ T helper 2 (Th2) cells, but is involved in a variety of processes such as immune regulation, proliferation and maintenance in other T cell and non-T cell lineages. 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). GATA3 has been shown to have many functional roles beyond controlling CD4+ Th2 cell differentiation These roles include the development of invariant NKT cells[5], the maturation and homing of natural killer (NK) cells[6] and the regulation and activation of CD8+ T cells[7]. PGC1α and GATA3 form a complex with the Serine/threonineprotein kinase ATR (ATR) and nuclear factor erythroid 2-related factor 2 (NRF2) to enhance mitochondrial biogenesis to maintain the viability of CD4+ T cells during DNA damage
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