60-kDa Tat-interactive Protein (TIP60) Positively Regulates Th-inducing POK (ThPOK)-mediated Repression of Eomesodermin in Human CD4+ T Cells

Abstract

The abundant expression of IFNγ in Th-inducing POK (ThPOK)-deficient CD4 + T cells requires the activation of Eomesodermin (Eomes); however, the underlying mechanism of this phenomenon remains unclear. Here we report that ThPOK binds directly to the promoter region of the Eomes gene to repress its expression in CD4 + T cells. We identified the histone acetyltransferase TIP60 as a co-repressor of ThPOK-target genes, where ectopically expressed TIP60 increased ThPOK protein stability by promoting its acetylation at its Lys 360 residue to then augment the transcriptional repression of Eomes. Moreover, knockdown of endogenous TIP60 abolished the stabilization of ThPOK in CD4 + T cells, which led to the transcriptional activation of Eomes and increased production of IFNγ. Our results reveal a novel pathway by which TIP60 and ThPOK synergistically suppresses Eomes function and IFNγ production, which could contribute to the regulation of inflammation. Background: ThPOK is required for CD4 + T helper cell differentiation and represses CD8 T cell-related genes, including Eomesodermin (Eomes) and IFNγ. Results: TIP60 stabilizes ThPOK by acetylation and augments ThPOK-mediated transcriptional repression of Eomes. Conclusion: TIP60 is a positive regulator of ThPOK. Significance: TIP60 could be a novel target for modulating IFNγ-mediated inflammation against cancer and virus infection.