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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

Authors

Andreas Begitt

Mathias Droescher

Thomas Meyer

Christoph D. Schmid

Michelle Baker

Filipa Antunes

Markus R. Owen

Ronald Naumann

Thomas Decker

Uwe Vinkemeier

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.

Journal Article Type Article
Journal Nature Immunology
Print ISSN 1529-2908
Electronic ISSN 1529-2916
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 15
Issue 2
Institution 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), doi:10.1038/ni.2794
DOI https://doi.org/10.1038/ni.2794
Publisher URL http://www.nature.com/ni/journal/v15/n2/full/ni.2794.html
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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