Promoter occupancy of STAT1 in interferon responses is regulated by processive transcription

Mol Cell Biol. 2015 Feb;35(4):716-27. doi: 10.1128/MCB.01097-14. Epub 2014 Dec 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line, Transformed
  • Embryo, Mammalian
  • Feedback, Physiological
  • Fibroblasts / cytology
  • Fibroblasts / immunology
  • Fibroblasts / metabolism*
  • Gene Expression Regulation
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / immunology
  • Interferon Regulatory Factor-1 / metabolism
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / genetics
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / immunology
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / metabolism
  • Interferon-beta / genetics
  • Interferon-beta / immunology
  • Interferon-beta / metabolism*
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Mice
  • Myxovirus Resistance Proteins / genetics
  • Myxovirus Resistance Proteins / immunology
  • Myxovirus Resistance Proteins / metabolism
  • Phosphorylation
  • Primary Cell Culture
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA, Messenger / genetics*
  • RNA, Messenger / immunology
  • RNA, Messenger / metabolism
  • STAT1 Transcription Factor / genetics*
  • STAT1 Transcription Factor / immunology
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Transcription, Genetic*

Substances

  • IRF9 protein, mouse
  • Interferon Regulatory Factor-1
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Irf1 protein, mouse
  • Mx2 protein, mouse
  • Myxovirus Resistance Proteins
  • RNA, Messenger
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Interferon-beta