The transcription factor ISGF3, comprised of IRF9 and tyrosine‐phosphorylated STATs 1 and 2, transmits the signal from the type I interferon receptor to the genome. We have discovered a novel phosphorylation of STAT2 on T387 that negatively regulates this response. In most untreated cell types, the majority of STAT2 is phosphorylated on T387 constitutively. In response to interferon‐β, the T387A mutant of STAT2 is much more effective than wild‐type STAT2 in mediating the expression of many interferon‐stimulated genes, in protecting cells against virus infection, and in inhibiting cell growth. Interferon‐β‐treated cells expressing wild‐type STAT2 contain much less ISGF3 capable of binding to an interferon‐stimulated response element than do cells expressing T387A STAT2. T387 lies in a cyclin‐dependent kinase (CDK) consensus sequence, and CDK inhibitors decrease T387 phosphorylation. Using CDK inhibitors to reverse the constitutive inhibitory phosphorylation of T387 of U‐STAT2 might enhance the efficacy of type I interferons in many different clinical settings.
An analysis by mass spectrometry revealed that the majority of STAT2 in cells is phosphorylated on T387 constitutively. This modification negatively regulates signaling responses to type I interferons. T387 lies in a consensus site for cyclin‐dependent kinases, suggesting that CDK inhibitors might augment responses to type I interferons.
STAT2 is phosphorylated on T387, which is located in the DNA‐binding domain.
STAT2 T387 phosphorylation negatively regulates type I IFN signaling.
The glucocorticoid signaling pathway affects T387 phosphorylation.
CDK inhibitors downregulate STAT2 T387 phosphorylation.
- Received May 23, 2016.
- Revision received October 6, 2016.
- Accepted October 11, 2016.
- © 2016 The Authors