Threonine phosphorylation of STAT1 restricts interferon signaling and promotes innate inflammatory responses

• 成果类型: Article
• 署名作者: Metwally, Hozaifa; Elbrashy, Maha M.; Ozawa, Tatsuhiko; Okuyama, Kazuki; White, Jason T.; Tulyeu, Janyerkye; Sondergaard, Jonas Norskov; Wing, James Badger; Muratsu, Arisa; Matsumoto, Hisatake; Ikawa, Masahito; Kishi, Hiroyuki; Taniuchi, Ichiro; Kishimoto, Tadamitsu
• 署名单位: University of Osaka; Egyptian Knowledge Bank (EKB); National Research Centre (NRC); University of Toyama; RIKEN; University of Osaka; University of Osaka; University of Osaka; University of Osaka; University of Osaka
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13714
• DOI: 10.1073/pnas.2402226121
• 发表日期: 2024-04-23
• 关键词: posttranslational modifications; PATHWAY; activation; expression; resistance; mechanism; genes; tyk2; ikk

摘要

Since its discovery over three decades ago, signal transducer and activator of scription 1 (STAT1) has been extensively studied as a central mediator for interferons (IFNs) signaling and antiviral defense. Here, using genetic and biochemical assays, we unveil Thr 748 as a conserved IFN - independent phosphorylation switch in Stat1, which restricts IFN signaling and promotes innate inflammatory responses following the recognition of the bacterial - derived toxin lipopolysaccharide (LPS). Genetically engineered mice expressing phospho - deficient threonine748 - to - alanine (T748A) mutant Stat1 are resistant to LPS - induced lethality. Of note, T748A mice exhibited undisturbed IFN signaling, as well as total expression of Stat1. Further, the T748A point mutation of Stat1 recapitulates the safeguard effect of the genetic ablation Stat1 following LPS - induced lethality, indicating that the Thr 748 phosphorylation contributes inflammatory functionalities of Stat1. Mechanistically, LPS - induced Toll - like receptor 4 endocytosis activates a cell - intrinsic I kappa B kinase - mediated Thr phosphorylation of Stat1, which promotes macrophage inflammatory response restricting the IFN and anti - inflammatory responses. Depletion of macrophages restores the sensitivity of the T748A mice to LPS - induced lethality. Together, our study indicates a phosphorylationdependent modular functionality of in innate immune responses: IFN phospho - tyrosine dependent and inflammatory phospho - threonine dependent. Better understanding of the Thr 748 phosphorylation of Stat1 may uncover advanced pharmacologically targetable molecules and better treatment modalities for sepsis, a disease that claims millions of lives annually.