アポプトティックカスパスはmtDNA誘発型STING媒介型I型IFN生成を抑制する

Michael J White¹, Kate McArthur¹, Donald Metcalf²

¹ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.

Cell

|December 20, 2014

まとめ

活性化されたカスパスは,アポトーシス中の免疫反応を防ぐ. カスパースの活動は,ミトコンドリアDNAの放出を抑制し,インターフェロン産生を止め,幹細胞を保護する.

科学分野:

免疫学免疫学とは
細胞生物学細胞生物学
分子生物学は分子生物学である.

背景:

活性化されたカスパスは,固有のアポトーシスの鍵ですが,体内の細胞死には不可欠ではありません.
死んでいる細胞は免疫反応を誘発し,カスパスが免疫調節作用を持つ可能性があることを示唆します.

研究の目的:

Bak/Bax媒介によるアポトーシス中の免疫応答を抑制するカスパースカスケードの役割を調査する.
カスパスが死にゆく細胞によるI型インターフェロン産生を阻害するかどうかを判断する.

主な方法:

カスペーゼ経路の成分 (カスペーゼ9,Apaf-1,カスペーゼ-3/7) の薬理学的カスペーゼ阻害と遺伝的削除を活用した.
ミトコンドリアDNAの放出とcGAS/STING依存のDNA感知経路の活性化を評価した.
測定されたインターフェロンベータ (IFN-β) 生産 in vitro と in vivo.
Bak/Bax媒介によるアポトーシスの存在における血液形成性幹細胞機能の評価.

主要な成果:

カスパースカスケードは,Bak/Bax媒介によるアポトーシスを受けている細胞におけるI型インターフェロン産生を抑制する.
カスパースの阻害またはデリエーションは,死にゆく細胞によるIFN-βの分泌につながります.
In vivoでは,このIFN-βの上昇は,血液生成幹細胞機能不全を引き起こす.
バックとバックスの喪失は,幹細胞の機能不全を修正する.

結論:

アポプトティックカスパースカスケードは,ミトコンドリアのアポトーシスを免疫学的に静止させます.
死亡する細胞によって引き起こされる炎症反応を防ぐために,カスパース活性が極めて重要です.
このメカニズムは,血液形成性幹細胞のような重要な細胞集団を,免疫媒介による損傷から保護します.

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