BAK/BAXマクロポールは,アポトーシス中のミトコンドリアヘルニアとmtDNA流出を促進する

Kate McArthur^1,2,3, Lachlan W Whitehead^4,2, John M Heddleston⁵

¹Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. kate.mcarthur@monash.edu benjamin.kile@monash.edu.

Science (New York, N.Y.)

|February 24, 2018

まとめ

死んでいる細胞はミトコンドリアDNA (mtDNA) を放出し,cGAS/STING経路を通じて先天的な免疫を誘発する. BAK/BAX孔はミトコンドリア内膜のヘルニアを許し,mtDNAを露出させ,タイプIインターフェロン信号を活性化します.

科学分野:

細胞生物学
免疫学
分子生物学

背景:

BAKとBAXタンパク質によるミトコンドリア外膜浸透 (MOMP) はアポトーシスを開始する.
活性キャスパスが欠けている死滅する細胞は,ミトコンドリアDNA (mtDNA) を通じてcGAS/STING先天免疫経路を活性化することができます.
mtDNAがcGASのような細胞センサーにアクセスするメカニズムは完全に理解されていません.

研究の目的:

ミトコンドリアDNA (mtDNA) がアポトーシス中に細胞溶液にどのようにアクセスするかを調査する.
mtDNA放出と先天的な免疫活性化におけるBAK/BAX毛穴の役割を明らかにする.

主な方法:

生細胞格子光シート顕微鏡を用いて,マウスの胚性線維細胞におけるミトコンドリアネットワークの動態を視覚化した.
この研究は,BAK/ BAX媒介による細胞のアポトーシスとシトクロームcの喪失に焦点を当てた.

主要な成果:

BAK/BAXの活性化により,ミトコンドリアのネットワークが崩壊し,外側のミトコンドリア膜に大きな毛穴が形成された.
これらのBAK/BAXマクロポールは,内部のミトコンドリア膜がシトソールに溶解することを促進した.
ミトコンドリアマトリックスの含有物 (mtDNAを含む) をシトゾールに放出し,cGAS/STING経路の活性化を可能にします.
アクティブなカスパスは細胞を分解し,潜在的にmtDNA誘発の免疫信号を抑制することが観察されました.

結論:

BAK/BAX媒介のマクロポールは,ミトコンドリア内膜ヘルニアとアポトーシス中のmtDNAの細胞溶解放出に不可欠である.
このヘルニア化メカニズムは,mtDNAが細胞性先天性免疫センサーにどのようにアクセスするかを説明します.
カスパスによる細胞分解は,自己DNAで引き起こされる炎症を制限するのに役立ちます.

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