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

Hozaifa Metwally*, Maha M. Elbrashy, Tatsuhiko Ozawa, Kazuki Okuyama, Jason T. White, Janyerkye Tulyeu, Jonas Nørskov Søndergaard, James Badger Wing, Arisa Muratsu, Hisatake Matsumoto, Masahito Ikawa, Hiroyuki Kishi, Ichiro Taniuchi, Tadamitsu Kishimoto*

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

3 被引用数 (Scopus)

抄録

Since its discovery over three decades ago, signal transducer and activator of transcription 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 Thr748 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 of Stat1 following LPS-induced lethality, indicating that the Thr748 phosphorylation contributes inflammatory functionalities of Stat1. Mechanistically, LPS-induced Toll-like receptor 4 endocytosis activates a cell-intrinsic IκB kinase-mediated Thr748 phosphorylation of Stat1, which promotes macrophage inflammatory response while 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 phosphorylation-dependent modular functionality of Stat1 in innate immune responses: IFN phospho-tyrosine dependent and inflammatory phospho-threonine dependent. Better understanding of the Thr748 phosphorylation of Stat1 may uncover advanced pharmacologically targetable molecules and offer better treatment modalities for sepsis, a disease that claims millions of lives annually.

本文言語英語
論文番号e2402226121
ジャーナルProceedings of the National Academy of Sciences of the United States of America
121
17
DOI
出版ステータス出版済み - 2024/04/23

ASJC Scopus 主題領域

  • 一般

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