title: 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.
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Ivana
authors.initials: I
authors.lastname: Wiesauer
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Clemens
authors.initials: C
authors.lastname: Gaumannmüller
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Iris
authors.initials: I
authors.lastname: Steinparzer
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria pavel.kovarik@univie.ac.at.
authors.forename: Pavel
authors.initials: P
authors.lastname: Kovarik
mesh_terms: D000818:Animals; D001665:Binding Sites; D002461:Cell Line, Transformed; D004622:Embryo, Mammalian; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D064547:Myxovirus Resistance Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D050856:Interferon Regulatory Factor-1; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016899:Interferon-beta; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494258:Irf1 protein, mouse; C579067:Mx2 protein, mouse; C494080:Stat1 protein, mouse; C494228:Isgf3g protein, mouse