Promoter Occupancy of STAT1 in Interferon Responses Is Regulated by Processive Transcription

Abstract

Interferons regulate immunity by inducing DNA binding of the transcription factor STAT1 through Y701 phosphorylation. Transcription by STAT1 needs to be restricted to minimize the adverse effects of prolonged immune responses. It remains unclear how STAT1 inactivation is regulated such that the transcription output is adequate. Here we show that efficient STAT1 inactivation in macrophages is coupled with processive transcription. Ongoing transcription feeds back to reduce the promoter occupancy of STAT1 and, consequently, the transcriptional output. Once released from the promoter, STAT1 is ultimately inactivated by Y701 dephosphorylation. We observe similar regulation for STAT2 and STAT3, suggesting a conserved inactivation mechanism among STATs. These findings reveal that STAT1 promoter occupancy in macrophages is regulated such that it decreases only after initiation of the transcription cycle. This feedback control ensures the fidelity of cytokine responses and provides options for pharmacological intervention.

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ACKNOWLEDGMENTS

We thank Marton Janos for critical reading of the manuscript.

This work was supported by Austrian Science Fund (FWF) grants W1220-B09 DP (Molecular Mechanisms of Cell Signaling), P22806-B11, and P27538-B21 to P.K., by Austrian Science Fund grant SFB-F28 to B.S., and by the European Union Seventh Framework Programme Marie Curie Initial Training Networks (FP7-PEOPLE-2012-ITN) for the project INBIONET under grant agreement PITN-GA-2012-316682.