カスパース-4非正規炎症体によるIL-18の認識と成熟
Xuyan Shi1, Qichao Sun2,3, Yanjie Hou2
1National Institute of Biological Sciences, Beijing, Beijing, P. R. China.
Nature
|November 22, 2023
まとめ
人間のカスパース-4はマウスカスパース-11とは異なり,重要なサイトカインであるIL-18を処理する. この発見により,非正規の炎症体機能とIL-18の関係が明らかになった.
科学分野:
- 免疫学
- 分子生物学
- 構造生物学
背景:
- カノニカル (カスペーゼ-1) と非カノニカル (カスペーゼ-4/5/11) の炎症ゾームはガスダーミンD (GSDMD) を割って,熱死を引き起こす.
- カスパース-1はIL-1βとIL-18を処理するが,リポポリサッカリドで活性化されたカスパース-4/5/11の標的はほとんど不明である.
- 非正規の炎症体標的の理解は,免疫と疾患の研究に不可欠です.
研究 の 目的:
- リポポリサッカリド活性化カスパース-4/5/11がIL-18を処理できるかどうかを判断する.
- カスパース-4/5/11とプロIL-18の相互作用の分子メカニズムを解明する.
- IL-18の処理における種別差異の構造的根拠を調査する.
主な方法:
- リコンビネントヒトカスパース-4とマウスカスパース-11を用いたインビトロ酵素測定
- カスパース-4-プロ-IL-18複合体の結晶構造の決定
- in vivoでIL-18の処理を評価するための細菌感染モデル.
主要な成果:
- 人間のカスパース-4は,マウスのカスパース-11とは異なり,プロIL-18をインビトロおよび細菌感染中に効率的に処理する.
- 結晶構造は,プロ-IL-18の触媒とエクソサイト相互作用を含むバイナリ基板認識メカニズムを示しています.
- カスパース-4,-5,および-1は,プロ-IL-18の類似のバイナリ認識を使用し,カスパース-11のエクソサイト偏差は結合を防ぐ.
- カスパース-1, -4,または -5による割れは,IL-18の構造変化を誘導し,受容体結合部位を生成する.
結論:
- IL-18は,リポポリサカリド活性化ヒトカスパース-4/5の直接標的として特定されています.
- この研究は,非正規の炎症体介護防御機構の理解におけるパラダイムシフトを明らかにしています.
- この発見は,免疫と疾患の病原性におけるIL-18の役割の理解を深めるものです.
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