Gene regulatory logic of the interferon-β enhancer is characterized by two selectively deployed modes of transcription factor synergy

• 成果类型: Article
• 署名作者: Schiffman, Allison; Cheng, Zhang; Ourthiague, Diana; Hoffmann, Alexander
• 署名单位: University of California System; University of California Los Angeles; University of California System; University of California Los Angeles
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11690
• DOI: 10.1073/pnas.25028001221
• 发表日期: 2025-08-12
• 关键词: nf-kappa-b; i interferon; crystal-structure; binding-activity; activation; expression; irf-3; induction; mechanism; ap-1

摘要

Type I interferon IFN beta is a key immune response cytokine, and when its expression is dysregulated, it causes disease. The regulation of IFN beta enhancer has been a touchpoint of mammalian gene control research since the discovery of functional synergy between two stimulus-responsive transcription factors (TFs), nuclear factor kappa B (NF kappa B) and interferon regulatory factors (IRF). However, subsequent gene knockout studies revealed that in some conditions either NF kappa B or IRF activation can be dispensable, leaving the precise regulatory logic of IFN beta transcription an open question. Here, we developed a series of quantitative enhancer states models of IFN beta expression control and evaluated them with stimulus-response data from TF knockouts. Of these, our analysis reveals that two modes of TF synergy account for the available data and neither is based on binding cooperativity. The first involves two adjacent IRF dimers, with a sigmoidal binding curve at the distal site rendering it ultrasensitive and restricting it to conditions of high IRF activity upon viral infection. The second is driven by the proximal site, which has high affinity and synergizes with NF kappa B to enable about half-maximal expression in response to bacterial exposure. Its accessibility is controlled by the competitive repressor p50:p50, which prevents basal IRF from binding, such that NF kappa B-only stimuli do not induce IFN beta expression and may allow for prior-exposure-dependent tuning. The model explains how the regulatory logic of the IFN beta enhancer ensures invariant IFN beta expression in response to viral exposure, while providing tunable, context-dependent expression in response to bacterial exposure.