IL-2 mRNA stabilization upon PMA stimulation is dependent on NF90-Ser ⁶⁴⁷ phosphorylation by protein kinase CβI

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 Ser⁶⁴⁷ 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 Ser⁶⁴⁷ 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-Ser⁶⁴⁷, 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.