Interferon-α-induced Expression of Phospholipid Scramblase 1 through STAT1 Requires the Sequential Activation of Protein Kinase Cδ and JNK*

Phospholipid scramblase 1 (PLSCR1), a calcium-binding protein that either inserts into the plasma membrane or binds to genomic DNA in the nucleus, has been shown to contribute to the cell proliferation, differentiation, and apoptosis as well as antiviral activity of interferon (IFN). The expression of PLSCR1 protein is also known to be markedly increased in response to IFN and to some differentiation inducing agents such as all-trans retinoic acid, but the precise mechanisms of this response remain to be investigated. In this study, we show that the protein kinase Cδ (PKCδ)-specific inhibitor rottlerin and the dominant negative mutant of PKCδ significantly antagonized IFN-induced PLSCR1 expression. The influence of PKCδ on IFN-mediated induction of PLSCR1 was dependent upon the phosphorylation of STAT1 at Ser-727. Furthermore, PKCδ-mediated activation of STAT1 required the activation of JNK, as the inhibition of JNK activity by its specific inhibitor or transfection of its dominant negative mutant suppressed both serine phosphorylation of STAT1 and PLSCR1 expression but not the activation of PKCδ. In conclusion, our results suggest that the induction of PLSCR1 transcription through STAT1 depends upon sequential activation of PKCδ and JNK.