Activation of Protein Kinase C{delta} by IFN-{gamma}

Engagement of the type II IFN (IFN-[gamma]) receptor results in activation of the Janus kinase-Stat pathway and induction of gene transcription via IFN- [gamma]-activated site (GAS) elements in the promoters of IFN-[gamma]-inducible genes. An important event in IFN-[gamma]-dependent gene transcription is phosphorylation of Stat1 on Ser super(727), which is regulated by a kinase activated downstream of the phosphatidylinositol 3'-kinase. Here we provide evidence that a member of the protein kinase C (PKC) family of proteins is activated downstream of the phosphatidylinositol 3'-kinase and is engaged in IFN-[gamma] signaling. Our data demonstrate that PKC[delta] is rapidly phosphorylated during engagement of the type II IFNR and its kinase domain is induced. Subsequently, the activated PKC[delta] associates with a member of the Stat family of proteins, Stat1, which acts as a substrate for its kinase activity and undergoes phosphorylation on Ser super(727). Inhibition of PKC[delta] activity diminishes phosphorylation of Stat1 on Ser super(727) and IFN-[gamma]-dependent transcriptional regulation via IFN-[gamma]-activated site elements, without affecting the phosphorylation of the protein on Tyr super(701). Thus, PKC[delta] is activated during engagement of the IFN-[gamma] receptor and plays an important role in IFN-[gamma] signaling by mediating serine phosphorylation of Stat1 and facilitating transcription of IFN-[gamma]-stimulated genes.