Phosphorylation of STAT2 on serine-734 negatively regulates the IFN-α-induced antiviral response

Abstract

Serine phosphorylation of STAT proteins is an important posttranslational 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 wildtype 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.

Fine-Tuning of Type I Interferon Response by STAT3

“…STAT1 and STAT2 are considered to be the primordial signal mediators of IFN-I, as genetic ablation (30–33), hypomorphic mutation (33–35) or functional inactivation (35–38) of either molecule severely impairs the induction of IFN-stimulated genes (ISG) and IFN-I-mediated antiviral response in mice and humans. Nevertheless, STAT2 has also been reported to negatively regulate IFN-I response, either by constitutive phosphorylation at T387 to block ISGF3 formation and its DNA binding (39) or by IFN-I-induced phosphorylation at S287 (40) or S734 (41) with mechanisms yet to be defined. Moreover, STAT2 can serve as an adaptor to bridge the interaction between USP18 and IFNAR2, which inhibits ligand binding to the receptor, resulting in decreased receptor dimerization and signaling (42).…”

Negative regulation of type I IFN signaling

“…In physiological conditions, the level of T387 phosphorylation diminishes over time after IFN‐β treatment, resulting in the activation of ISGF3 complex . Furthermore, another group discovered that type I IFN induced phosphorylation of serine (S) 287 and S734 of STAT2 negatively regulates type I IFN signaling; however, the detailed mechanisms and differences for S287 and S734 of STAT2 phosphorylation are not clarified yet …”

CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci

“…However, whether STAT Ser phosphorylation promotes a positive or negative effect on STAT transcriptional activities remains more controversial ( Bancerek et al., 2013 ; Decker and Kovarik, 2000 ; Levy and Darnell, 2002 ; Lim and Cao, 1999 ). Some studies report a positive effect of STAT Ser phosphorylation in driving STAT transcriptional activities, whereas others have reported an opposite effect ( Bancerek et al., 2013 ; Decker and Kovarik, 2000 ; Levy and Darnell, 2002 ; Lim and Cao, 1999 ; Steen et al., 2016 ; Wen et al., 1995 ; Yokogami et al., 2000 ). For STAT3, Ser phosphorylation appears to negatively impact its transcriptional activities by regulating its chromatin binding dwell time ( Yang et al., 2020 ).…”