ミトコンドリアのストレスは,OMA1-DELE1-HRI経路によってサイトゾールに伝達される

Xiaoyan Guo^1,2, Giovanni Aviles^1,2, Yi Liu³

¹Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA.

Nature

|March 6, 2020

まとめ

ミトコンドリアのストレスは,OMA1-DELE1-HRI経路を活性化し,eIF2αリン酸化経由でATF4を誘導する信号をリレーします. この経路は哺乳類の細胞の統合ストレス反応に不可欠です

科学分野:

細胞生物学
ストレス反応の分子メカニズム

背景:

ミトコンドリア機能障害は,哺乳類の細胞における統合ストレス反応 (ISR) を活性化させる.
ユカリオット翻訳開始因子2α (eIF2α) のリン酸化は,ISR中にATF4誘導につながる.
ミトコンドリアのストレスをATF4に伝達する正確なメカニズムは不明のままです.

研究の目的:

ATF4誘導にミトコンドリアのストレスを伝達する信号経路を特定する.
このストレス反応経路におけるHRI,OMA1,DELE1の役割を解明する.

主な方法:

アップストリーム要因を特定するための全ゲノムCRISPR干渉スクリーニング
タンパク質の相互作用とキナーゼ活性の研究のための生化学的測定.
ATF4変換と統合ストレス反応の活性化の分析

主要な成果:

HRI (血液調節阻害剤) は,ミトコンドリアストレスを伝達する重要なeIF2αキナーゼとして特定されました.
OMA1 (プロテアゼ) とDELE1 (ミトコンドリアタンパク質) は,HRIの前流で機能する.
ミトコンドリアのストレスはOMA1依存のDELE1分裂を誘発し,細胞性DELE1の蓄積とHRIの活性化につながります.
DELE1は,eIF2αのリン酸化後のATF4変換に不可欠である.
OMA1-DELE1-HRI経路の阻害は,代替のチャペロン反応を誘導する.

結論:

OMA1-DELE1-HRI経路は,ATF4へのミトコンドリアストレスの主要なリレーです.
この経路は,ミトコンドリア機能不全に関連した疾患においてISRを調節するための潜在的な治療目標です.

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