Serine phosphorylation of STAT proteins is an important post-translational modification event that, in addition to tyrosine phosphorylation, is required for strong transcriptional activity. However, we recently showed that phosphorylation of STAT2 on S287 induced by type I interferons (IFN-α and IFN-β), evoked the opposite effect. S287-STAT2 phosphorylation inhibited the biological effects of IFN-α. We now report the identification and characterization of S734 on the C-terminal transactivation domain of STAT2 as a new phosphorylation site that can be induced by type I IFNs. IFN-α-induced S734-STAT2 phosphorylation displayed different kinetics to that of tyrosine phosphorylation. S734-STAT2 phosphorylation was dependent on STAT2 tyrosine phosphorylation and JAK1 kinase activity. Mutation of S734-STAT2 to alanine (S734A) enhanced IFN-α-driven antiviral responses compared to those driven by wild-type STAT2. Furthermore, DNA microarray analysis demonstrated that a small subset of type I IFN stimulated genes (ISGs) was induced more by IFNα in cells expressing S734A-STAT2 when compared to wild-type STAT2. Taken together, these studies identify phosphorylation of S734-STAT2 as a new regulatory mechanism that negatively controls the type I IFN-antiviral response by limiting the expression of a select subset of antiviral ISGs.
The authors declare no competing or financial interests.
A.M.G. prepared the manuscript and designed experiments; H.C.S. and K.P.K. conducted and designed experiments, and helped write the manuscript; S.N. and M.Y.H. conducted some of the experiments, and S.B. helped with manuscript preparation and experimental design.
This project was supported by grants to A.M.G. from the National Cancer Institute (RO1CA140499) and the Pennsylvania Department of Health. Deposited in PMC for release after 12 months.
The microarray data reported in this study are available from the Gene Expression Omnibus database under accession number GSE57017 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE57017).
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.185421.supplemental
- Received December 23, 2015.
- Accepted September 19, 2016.
- © 2016. Published by The Company of Biologists Ltd