STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling

Begitt, Andreas; Droescher, Mathias; Meyer, Thomas; Schmid, Christoph D.; Baker, Michelle; Antunes, Filipa; Owen, Markus R.; Naumann, Ronald; Decker, Thomas; Vinkemeier, Uwe

Abstract

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.

Citation

Begitt, A., Droescher, M., Meyer, T., Schmid, C. D., Baker, M., Antunes, F., …Vinkemeier, U. (in press). STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling. Nature Immunology, 15(2), https://doi.org/10.1038/ni.2794

• Journal Article Type: Article
• Acceptance Date: Nov 18, 2013
• Online Publication Date: Jan 12, 2014
• Deposit Date: Aug 4, 2016
• Journal: Nature Immunology
• Print ISSN: 1529-2908
• Electronic ISSN: 1529-2916
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 2
• DOI: https://doi.org/10.1038/ni.2794
• Public URL: https://nottingham-repository.worktribe.com/output/721859
• Publisher URL: http://www.nature.com/ni/journal/v15/n2/full/ni.2794.html