MicroRNA-34a Enhances T Cell Activation by Targeting Diacylglycerol Kinase ζ

The engagement of the T cell receptor (TCR) induces the generation of diacylglycerol (DAG), an important second messenger activating both the Ras/Erk and PKC theta/NF kappa B pathways. DAG kinases (DGKs) participate in the metabolism of DAG by converting it to phosphatidic acid. DGK zeta has been demonstrated to be able to inhibit DAG signaling following TCR engagement. Deficiency of DGK zeta increases the sensitivity of T cells to TCR stimulation, resulting in enhanced T cell activation ex vivo and in vivo. However, the mechanisms that control DGK zeta expression are poorly understood. Here we demonstrate that DGK zeta mRNA is a direct target of a cellular microRNA miR-34a. The DGK zeta transcript is decreased, whereas the primary miR-34a is upregulated upon TCR stimulation. Ectopic miR-34a expression suppresses DGK zeta protein expression through the seed match binding to both the 3' untranslated region and coding region of DGK zeta mRNA, leading to increased ERK1/2 phosphorylation and surface expression of the T cell activation marker CD69 following TCR cross-linking. In contrast, overexpression of a miR-34a competitive inhibitor increases DGK zeta expression and suppresses TCR-mediated T cell activation. Together, our data demonstrate that miR-34a is a negative regulator for DGK zeta and may play an important role in regulating T cell activation.