SARS-CoV-2のNsp1タンパク質によるトランスレーション停止と免疫回避の構造的基礎
Matthias Thoms1, Robert Buschauer1, Michael Ameismeier1
1Gene Center Munich, Department of Biochemistry, University of Munich, Munich, Germany.
Science (New York, N.Y.)
|July 19, 2020
まとめ
重症急性呼吸器症候群コロナウイルス2 (SARS-CoV-2) の非構造タンパク質1 (Nsp1) は40Sリボソームサブユニットと結合し,宿主遺伝子翻訳を停止する. Nsp1に関する構造的な洞察
科学分野:
- 分子生物学
- ウイルス学
- 構造生物学
背景:
- 重症急性呼吸器症候群コロナウイルス2型 (SARS-CoV-2型) がCOVID-19のパンデミックを引き起こす.
- 非構造タンパク質1 (Nsp1) は,宿主遺伝子の発現を抑制する重要なSARS-CoVの毒性因子である.
- Nsp1はリボソームと結合してタンパク質合成を阻害する.
研究 の 目的:
- SARS-CoV-2 Nsp1が宿主トランスレーションを阻害する分子メカニズムを解明する.
- Nsp1-リボソームの相互作用の構造的基礎を決定する.
- 宿主の先天的な免疫反応を回避する Nsp1 の役割を調査する.
主な方法:
- Nsp1-リボソーム複合体の構造を決定するために,冷凍電子顕微鏡 (cryo-EM) が使用された.
- Nsp1- 40S複合体の in vitro 溶解
- mRNA翻訳と先天的免疫に対するNSP1の影響を評価するための細胞ベースの測定法.
主要な成果:
- SARS-CoV-2 Nsp1は40Sリボソームサブユニットと結合する.
- Nsp1結合は,インビトロと細胞システムの両方でmRNA翻訳の停止につながります.
- 構造分析により,Nsp1 C端がリボソームのmRNA入口トンネルを阻害することが明らかになった.
- Nsp1媒介による翻訳阻害は,網膜酸誘導性遺伝子I (RIG- I) に依存する先天免疫反応を阻害する.
結論:
- SARS-CoV-2 Nsp1のC末端領域は,リボソームのmRNAエントリートンネルを遮断することによって宿主トランスレーションを阻害するために重要である.
- Nsp1の作用メカニズムは,ウイルスのクリアランスに不可欠な先天的な免疫信号伝達経路を効果的に抑制します.
- Nsp1の構造と機能の関係を理解することは,SARS-CoV-2に対する構造ベースの抗ウイルス薬の開発の基盤を提供します.
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