title: Phosphorylation of STAT2 on serine-734 negatively regulates the IFN-α-induced antiviral response.
abstract: 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.
authors: Dept. of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
authors: Håkan C
authors: HC
authors: Steen
authors: Dept. of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
authors: Kevin P
authors: KP
authors: Kotredes
authors: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors: Shoko
authors: S
authors: Nogusa
authors: Dept. of Anatomy and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
authors: Michele Y
authors: MY
authors: Harris
authors: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors: Siddharth
authors: S
authors: Balachandran
authors: Dept. of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA gameroa@temple.edu.
authors: Ana M
authors: 0000-0001-7843-1415
authors: AM
authors: Gamero
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D050795:STAT2 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D018116:Vesiculovirus / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D050795:STAT2 Transcription Factor; D012694:Serine; D053612:Janus Kinases
keywords: Interferon; JAK1; STAT2; Serine phosphorylation; Vesicular stomatitis; Virus infection