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IL-2 is an important cytokine produced in T cells in response to Ag or mitogen stimulation. It is regulated at both transcriptional and posttranscriptional levels. One of the key regulators of IL-2 mRNA stability is NF90. Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it. Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser(647) and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA. Phorbol ester (PMA) is a protein kinase C (PKC) activator. Through transcription activation and mRNA stabilization, IL-2 mRNA levels increase promptly when T cells are stimulated with PMA. However, how PMA stabilizes IL-2 mRNA was still unclear. In this study, we demonstrate that PMA stimulation led to phosphorylation of NF90 at Ser(647) via PKCβI. This phosphorylation was necessary for nuclear export of NF90 in response to PMA and for IL-2 mRNA stabilization. We show that phosphorylation at NF90-Ser(647) upregulated IL-2 production in response to PMA stimulation. Our results support a model in which PMA stimulation activates PKCβI to phosphorylate NF90-Ser(647), and this phosphorylation triggers NF90 relocation to the cytoplasm and stabilize IL-2 mRNA. Thus, our study elucidates the mechanism by which PMA activates and stabilizes IL-2 expression in T cells.

IL-2 mRNA Stabilization upon PMA Stimulation Is Dependent on NF90-Ser647 Phosphorylation by Protein Kinase CβI