Molecular Mechanism Of PMA Regulating Immune Factor IL - 2mRNA Stabilization

Interleukin-2 (IL-2) is an important cytokine produced in T cells in response to antigen or mitogen stimulation. It is regulated at both transcriptional and post-transcriptional levels. IL-2 mRNAs is a labile transcript containing AU-rich elements (ARE) in their 3 untranslated region. The ARE-binding proteins (AUBPs) binding to them and promote or repress their degradation. 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 ARE-containing 3 untranslated regions of IL-2 mRNA and stabilizes it. Our previous work showed that CD28 co-stimulation 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 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-Ser647 up-regulated 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.