クラトリン関連AP-1はSTING信号の終了を制御する
Ying Liu1, Pengbiao Xu1, Sophie Rivara1
1Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
Nature
|October 19, 2022
まとめ
アダプタータンパク質複合体1 (AP-1) は,インターフェロン遺伝子の刺激器 (STING) 免疫シグナリングを終了させます. AP-1はリン酸化したSTINGを分解し,一時的な免疫活性化と自己炎症を防止します.
科学分野:
- 免疫学
- 分子生物学
- 細胞生物学
背景:
- インターフェロン遺伝子の刺激剤 (STING) は,DNAと細菌の周期性ダイヌクレオチドに反応し,先天的な免疫に不可欠です.
- 免疫反応のバランスと自己炎症を避けるには,STING活性化の正確な調節が不可欠です.
- ゴルギ装置のSTING信号を終了するメカニズムは不明のままでした.
研究 の 目的:
- STING依存の免疫活性化を終結させるメカニズムを解明する.
- STING信号の終了に関与する分子プレーヤーとモチーフを特定する.
主な方法:
- クリオ電子顕微鏡で,リン酸化STINGに結合したAP-1の構造を決定する.
- STING C端尾の保存されたモチーフの分析
- STINGシグナル伝達への影響を観察するためにAP-1抑制を含む実験.
主要な成果:
- アダプタータンパク質複合体1 (AP-1) は,STING信号の終結を媒介する.
- AP-1は,酸化されたSTINGを,内溶性分解のためにクラトリンで覆われた小胞に分類する.
- 保存されたディレウシンモチーフとSTINGのC端尾のTBK1依存のリン酸化はAP-1結合に不可欠である.
- Cryo-EMはAP-1によって活性化されたSTINGの認識を強化するための構造的基礎を明らかにしました.
- AP-1を抑制すると,STING誘発の免疫反応が悪化する.
結論:
- AP-1は,STINGシグナリングのネガティブレギュレータとして,それを分解するためにターゲットを設定します.
- ディレウシンモチーフとリン酸化はAP-1の結合部位を作り,STINGの活性化と終結を結びます.
- このメカニズムは一時的な免疫活性化を保証し,有害な自己炎症を予防します.
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