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ヒトのADAR1は内生RNAがトランスレーション停止を誘発するのを防ぐ

Hachung Chung¹, Jorg J A Calis², Xianfang Wu¹

¹Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.

|February 4, 2018

まとめ

ADAR1酵素は,自己RNAが二重鎖RNA (dsRNA) を編集することで免疫反応を誘発することを防ぐ. ADAR1のノックアウト細胞は,自発的なインターフェロン産生を示し,自己核酸と非自己核酸の区別におけるその役割を強調する.

科学分野:

免疫学
分子生物学
遺伝学

背景:

タイプIインターフェロン (IFN) の生成は,外来核酸を検出する宿主センサーによって誘発されます.
これらのセンサーが自己と非自己の二重鎖RNA (dsRNA) を区別するメカニズムは不明である.
dsRNAを編集する酵素であるADAR1の変異は,自己炎症と神経学的問題によって特徴づけられるAicardi-Goutières症候群と関連しています.

研究の目的:

人体細胞におけるADAR1の基板と機能を研究する.
ADAR1が自己と非自己の核酸を区別する方法を理解する.
インターフェロン反応の調節と自己炎症の予防におけるADAR1の役割を明らかにする.

主な方法:

機能研究のためのADAR1ノックアウトヒト細胞を生成した.
RNAポリメラーゼII (pol II) とpol IIIのトランスクリプトにおけるADAR1編集活性を分析した.
IFN応答中のPKR活性化と翻訳停止に対するADAR1の影響を評価した.
神経元細胞におけるMDA5依存型インターフェロン産生におけるADAR1の役割を調査した.

主要な成果:

ADAR1は主にpol IIで転写されたmRNAのAlu要素を編集し,pol IIIで転写されたAlusではない.
ADAR1はdsRNAセンサPKRの過剰活性化を阻害し,IFN応答中の翻訳停止を防止しました.
dsRNA結合とADAR1の触媒活動は,内生RNAがPKRを活性化するのを防ぐために不可欠でした.
ADAR1 ノックアウトニューロンの原始細胞は,自発的なMDA5依存インターフェロン産生,PKR活性化,細胞死を示した.

結論:

人間のADAR1は,自己対非自己RNAの感受を調節する上で重要な役割を果たします.
ADAR1は有害な自己炎症反応を予防しながら,病原体検出を可能にします.
ADAR1の調節不良は,自己RNA耐性を損なうことで,自己炎症状態に寄与する.

キーワード:

ADAR1 について AGS についてエイカルディ・グーティエール症候群アルウエレメント MDA5 について PKR について RNA編集生まれつきの免疫ニューロンの原始細胞翻訳 I型インターフェロン

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