Varinou et al. Phosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-gamma-dependent innate immunity. Immunity 2003:19:793-802.

Abstract

Many cytokine receptors activate Janus kinases (JAKs), which phosphorylate 1 or more receptor chains to create docking sites for signal transducers and activators of transcription (STATs). The conventional view concerning cytokine receptor signaling is that STATs are phosphorylated on a single tyrosine residue by JAKs. This leads STATs to disengage from the cytokine receptor and to subsequently dimerize, thereby gaining ability to access to the nucleus and activate gene transcription. However, certain STATs (1, 3, 4, and 5) are also phosphorylated on a serine residue located in the C-terminal transactivation domain. In the present paper, the investigators generated mice that contained a serine→alanine mutation at this serine residue (amino acid 727). These mice were susceptible to experimental bacterial challenge and were resistant to LPS-induced septic shock syndrome, suggesting that STAT1 serine phosphorylation promoted protective immunity and inflammation. Evidence was presented that the mechanism involved defective recruitment of histone acetylases to activated STAT1. These results provide a new paradigm concerning the mechanism of cytokine receptor signaling involving certain STATs. Many cytokine receptors activate Janus kinases (JAKs), which phosphorylate 1 or more receptor chains to create docking sites for signal transducers and activators of transcription (STATs). The conventional view concerning cytokine receptor signaling is that STATs are phosphorylated on a single tyrosine residue by JAKs. This leads STATs to disengage from the cytokine receptor and to subsequently dimerize, thereby gaining ability to access to the nucleus and activate gene transcription. However, certain STATs (1, 3, 4, and 5) are also phosphorylated on a serine residue located in the C-terminal transactivation domain. In the present paper, the investigators generated mice that contained a serine→alanine mutation at this serine residue (amino acid 727). These mice were susceptible to experimental bacterial challenge and were resistant to LPS-induced septic shock syndrome, suggesting that STAT1 serine phosphorylation promoted protective immunity and inflammation. Evidence was presented that the mechanism involved defective recruitment of histone acetylases to activated STAT1. These results provide a new paradigm concerning the mechanism of cytokine receptor signaling involving certain STATs.