ウイルスおよびメタゾアンの毒素は,cGAMP特異的な核酸で,cGAS-STINGシグナル伝達を制限する
James B Eaglesham1,2,3, Youdong Pan4, Thomas S Kupper4,5
1Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
Nature
|February 8, 2019
まとめ
ポックスウイルス免疫ヌクレアゼ (毒素) 退化 2
科学分野:
- 免疫学
- ウイルス学
- 構造生物学
背景:
- 細胞塩基DNAは,サイクルGMP-AMP合成酵素 (cGAS) と2',3'-サイクルGMP-AMP (cGAMP) を通して先天的な免疫を活性化します.
- STING経路は免疫シグナル伝達に不可欠ですが,2',3'-cGAMPの内生性阻害剤は知られていません.
- ウイルスは宿主の先天的な免疫反応を回避するメカニズムを進化させた.
研究 の 目的:
- 2',3'-cGAMPを分解する宿主またはウイルス要因を特定する.
- 新しい2',3'-cGAMP分解酵素の機能とメカニズムを特徴付ける.
- これらの酵素がウイルス病原化と先天性免疫回避における役割を調査する.
主な方法:
- 哺乳類ウイルスの生化学的スクリーニング
- 2',3'-cGAMPの分解に対する酵素活性測定法
- ワクチンウイルスの毒素の結晶構造の決定
- ワクチンウイルスの遺伝子消去研究
- 昆虫とバキュロウイルスにおける毒素同類のバイオ情報分析
主要な成果:
- ポックスウイルス免疫核酵素 (毒素) は2',3'-cGAMPを分解する酵素として識別された.
- 毒素は2',3'-cGAMPを分裂し,STING依存のシグナリングを制限する.
- ワクチンウイルスの毒素遺伝子 (B2R) を削除すると,ウイルスの複製がin vivoで減少した.
- 結晶構造は,選択的な2',3'-cGAMP水解のための金属独立メカニズムを明らかにした.
- 保存されたポキシンホモログは,昆虫のポキシンウイルスと宿主で発見され,古代の役割を示唆しています.
結論:
- 毒素は,2',3'-cGAMP特異的な核酸の新しい家族を表しています.
- ウイルスはポキシンを使って2',3'-cGAMPを分解し,cGAS-STING媒介の先天的免疫を回避する.
- 毒素はポックスウイルス病原性において重要な役割を果たし,cGAS-STING調節に関連した古くからの進化の歴史を持っています.
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