STAT2 Is a Pervasive Cytokine Regulator due to Its Inhibition of STAT1 in Multiple Signaling Pathways

Stat2 is the quintessential transcription factor for type 1 interferons (ifns),where it functions as a heterodimer with stat1. however,the human and murine stat2-deficient phenotypes suggest important additional and currently unidentified type 1 ifn-independent activities. here,we show that stat2 constitutively bound to stat1,but not stat3,via a conserved interface. while this interaction was irrelevant for type 1 interferon signaling and stat1 activation,it precluded the nuclear translocation specifically of stat1 in response to ifn-γ,interleukin-6 (il-6),and il-27. this is explained by the dimerization between activated stat1 and unphosphorylated stat2,whereby the semiphosphorylated dimers adopted a conformation incapable of importin-α binding. this,in turn,substantially attenuated cardinal ifn-γ responses,including mhc expression,senescence,and antiparasitic immunity,and shifted the transcriptional output of il-27 from stat1 to stat3. our results uncover stat2 as a pervasive cytokine regulator due to its inhibition of stat1 in multiple signaling pathways and provide an understanding of the type 1 interferon-independent activities of this protein. © 2016 ho et al.