TMEM106Bは,ACE2独立のSARS-CoV-2細胞の侵入を媒介する受容体である
Jim Baggen1, Maarten Jacquemyn1, Leentje Persoons1
1KU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Leuven 3000, Belgium.
Cell
|July 8, 2023
まとめ
研究者らは,TMEM106Bが,ACE2が欠けている細胞へのSARS-CoV-2の代替受容体として作用することを発見した. この発見は,SARS-CoV-2感染の新たなメカニズムと潜在的な治療標的を明らかにしています.
科学分野:
- ウイルス学
- 細胞生物学
- 構造生物学
背景:
- SARS-CoV-2は,宿主細胞の侵入受容体の可用性によって影響を受け,広範な組織トロピズムを示します.
- アンジオテンシン変換酵素2 (ACE2) は,SARS-CoV-2の侵入の主要な知られた受容体である.
- ウイルスの拡散を防ぐために 代替の侵入経路を理解することは 極めて重要です
研究 の 目的:
- ACE2を超えるSARS-CoV-2の侵入のための代替細胞受容体を特定する.
- TMEM106BとのSARS-CoV-2の相互作用のメカニズムを解明する.
- ウイルスの融合と感染における TMEM106B の役割を調査する.
主な方法:
- 構造的相互作用を決定するために,X線結晶学と冷凍電子顕微鏡 (cryo-EM) を利用した.
- タンパク質のダイナミクスを分析するために,水素-デュテリウム交換質量スペクトロメトリ (HDX-MS) を使用した.
- ウイルス感染を阻害するTMEM106B特異のモノクローナル抗体の有効性を試験した.
主要な成果:
- リンソーム型トランスメブランタンパク質であるTMEM106Bを,ACE2陰性細胞における代替のSARS-CoV-2エントリー受容体として特定した.
- 特定のスパイク変異 (E484D) がTMEM106Bの結合とウイルスの侵入を促進することを実証した.
- TMEM106Bに特異的な抗体はSARS-CoV-2感染を抑制することを示した.
- 構造分析により,TMEM106B 光領域はSARS-CoV-2 スパイク受容体結合モチーフと相互作用することが明らかになった.
- TMEM106Bはスパイク媒介のシンチウム形成を促進し,ウイルスの融合に役割を果たしていることが観察されました.
結論:
- TMEM106BはACE2独立のSARS-CoV-2の侵入を媒介する.
- ヘパラン硫酸とTMEM106Bの相互作用は,SARS-CoV-2感染を促進する.
- TMEM106Bは,SARS-CoV-2に対する抗ウイルス戦略の新たなターゲットです.
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