It is well established that engagement of the Type I interferon (IFN) receptor results in activation of JAKs (Janus kinases), which in turn regulate tyrosine phosphorylation of STAT proteins. Subsequently, the IFN-dependent tyrosine-phosphorylated/activated STATs translocate to the nucleus to regulate gene transcription. In addition to tyrosine phosphorylation, phosphorylation of Stat1 on serine 727 is essential for induction of its transcriptional activity, but the IFNα-dependent serine kinase that regulates such phosphorylation remains unknown. In the present study we provide evidence that PKC-δ, a member of the protein kinase C family of proteins, is activated during engagement of the Type I IFN receptor and associates with Stat1. Such an activation of PKC-δ appears to be critical for phosphorylation of Stat1 on serine 727, as inhibition of PKC-δ activation diminishes the IFNα- or IFNβ-dependent serine phosphorylation of Stat1. In addition, treatment of cells with the PKC-δ inhibitor rottlerin or the expression of a dominant-negative PKC-δ mutant results in inhibition of IFNα- and IFNβ-dependent gene transcription via ISRE or GAS elements. Interestingly, PKC-δ inhibition also blocks activation of the p38 MAP kinase, the function of which is required for IFNα-dependent transcriptional regulation, suggesting a dual mechanism by which this kinase participates in the generation of IFNα responses. Altogether, these findings indicate that PKC-δ functions as a serine kinase for Stat1 and an upstream regulator of the p38 MAP kinase and plays an important role in the induction of Type I IFN-biological responses.
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Published, JBC Papers in Press, February 11, 2002, DOI 10.1074/jbc.M109671200
This work was supported by National Institutes of Health Grants CA77816 and CA73381 (to L. C. P.), a Merit Review grant from the Department of Veterans Affairs (to L. C. P.), and Canadian Institutes of Health Research Grant MOP15094 (to E. N. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
