2022-09-26 バッファロー大学(UB)
N61とN801がスパイクタンパク質を適切な形に折り畳むのに一役買っている可能性がある。
フォールディングの仕組みを解明するため、研究チームは、スパイクの合成を助けるさまざまな細胞内糖鎖結合型「シャペロン」や「レクチン」の役割を調べた。その結果、カルネキシンと呼ばれる「シャペロン」タンパク質が、この種の折り畳みを促進し、宿主細胞へのVLPの侵入を制御していることが判明した。
<関連情報>
- https://www.buffalo.edu/news/releases/2022/09/025.html
- https://www.science.org/doi/10.1126/sciadv.abq8678
SARS-CoV-2 スパイクの成熟とウイルス感染性におけるN-グリカンとカルネキシン-カルレティキュリンのシャペロンの役割 Role for N-glycans and calnexin-calreticulin chaperones in SARS-CoV-2 Spike maturation and viral infectivity
Qi Yang,Anju Kelkar,Anirudh Sriram,Ryoma Hombu,Thomas A. Hughes,Sriram Neelamegham
Science Advances Published:23 Sep 2022
DOI: 10.1126/sciadv.abq8678
Abstract
Functional and epidemiological data suggest that N-linked glycans on the SARS-CoV-2 Spike protein may contribute to viral infectivity. To investigate this, we created a panel of N-to-Q mutations at N-glycosylation sites proximal to the Spike S1-S2 (N61, N603, N657, and N616) and S2′ (N603 and N801) proteolysis sites. Some of these mutations, particularly N61Q and N801Q, reduced Spike incorporation into Spike-pseudotyped lentivirus and authentic SARS-CoV-2 virus-like particles (VLPs). These mutations also reduced pseudovirus and VLP entry into ACE2-expressing cells by 80 to 90%. In contrast, glycan mutations had a relatively minor effect on cell surface expression of Spike, ACE2 binding, and syncytia formation. A similar dichotomy in function was observed when virus was produced in host cells lacking ER chaperones, calnexin and calreticulin. Here, while both chaperones regulated pseudovirus function, only VLPs produced in calnexin KOs were less infectious. Overall, Spike N-glycans are likely critical for SARS-CoV-2 function and could serve as drug targets for COVID-19.
