The interferon (IFN)-inducible protein kinase PKR is thought to mediate the biological effects of IFNs through its ability to phosphorylate eukaryotic initiation factor 2 and to inhibit protein synthesis. Additional reports have implicated PKR in transcriptional regulation. In this study, a role for PKR in the regulation of signal transduction pathways that are required for IFN action was examined. It is demonstrated that PKR negatively regulates signaling pathways induced by IFNs and dsRNA. This regulatory effect is attributed to a protein-protein interaction between PKR and STAT1, the signaling component common to these pathways, that impairs STAT1 transcriptional function. The interaction between PKR and STAT1 is not a kinase-substrate relationship since PKR does not phosphorylate STAT1 and both wildtype and catalytically inactive PKR can interact with STAT1. It is also shown that PKR regulates STAT1 protein expression. The regulatory effect does not occur at the transcriptional or post-transcriptional level since STAT1 mRNA transcription and stability are unaffected by PKR. Regulation of STAT1 expression is specific for STAT1 since expression of other STATs is not affected by PKR. The ability of PKR to regulate STAT1 function and expression has important implications in the control of gene expression, viral immunity, and cell growth.

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