STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling
Begitt, Andreas and Droescher, Mathias and Meyer, Thomas and Schmid, Christoph D. and Baker, Michelle and Antunes, Filipa and Owen, Markus R. and Naumann, Ronald and Decker, Thomas and Vinkemeier, Uwe (2014) STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling. Nature Immunology, 15 (2). pp. 168-176. ISSN 1529-2916
STAT1 is an indispensable component of a heterotrimer (ISGF3) and a STAT1 homodimer (GAF) that function as transcription regulators in type 1 and type 2 interferon signaling, respectively. To investigate the importance of STAT1-cooperative DNA binding, we generated gene-targeted mice expressing cooperativity-deficient STAT1 with alanine substituted for Phe77. Neither ISGF3 nor GAF bound DNA cooperatively in the STAT1F77A mouse strain, but type 1 and type 2 interferon responses were affected differently. Type 2 interferon–mediated transcription and antibacterial immunity essentially disappeared owing to defective promoter recruitment of GAF. In contrast, STAT1 recruitment to ISGF3 binding sites and type 1 interferon–dependent responses, including antiviral protection, remained intact. We conclude that STAT1 cooperativity is essential for its biological activity and underlies the cellular responses to type 2, but not type 1 interferon.
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