Evidence for phospho-tyrosine independent signalling activity of STAT1

The Jak-Stat signaling pathway regulates cellular responses to cytokines. Stat1 plays a crucial role in host defense by mediating the effects of interferons (IFNs). In the canonical signaling pathway, IFNs activate STAT1 through phosphorylation at Y701. This leads to the formation of dimers that are competent to translocate to the cell nucleus, bind DNA and stimulate expression of interferon induced genes (ISGs). As reported, Stat1 also participates in a non-canonical signaling pathway that is independent of Y701 phosphorylation. In the presented study, this possibility was analysed by investigation of antibacterial immunity in mice expressing mutant Stat1Y701F. Our work suggests a minor, but significant contribution of Stat1Y701F to the clearance of Listeria monocytogenes. Extensive analysis of Stat activation and gene expression patterns demonstrate clear differences between macrophages lacking Stat1 and those expressing Stat1Y701F, revealing a new putative mechanism of Stat1Y701F engagement in expression of ISGs. In summary our results provide clear evidence for biological activity of Stat1 in absence of its tyrosine phosphorylation.