SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to down-regulate MHC-I surface expression.
SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to down-regulate MHC-I surface expression.
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DOI：
10.1073/pnas.2208525120
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发表时间：
2023-01-03
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
病毒可以下调感染细胞上的MHC I类表达以避免被细胞毒性T细胞消除。我们报道了SARS-CoV-2的辅助蛋白ORF 7a和ORF 3a介导了这一功能，并描述了两种不同的机制。虽然ORF 3a抑制整体蛋白运输至细胞表面，但ORF 7a通过与β 2 m竞争结合至MHC-I重链而特异性作用于MHC-I。这是第一次将β 2 m的分子模拟作为MHC-I下调以促进免疫逃避的病毒机制。主要组织相容性复合物I类（MHC-I）分子是糖基化多态性跨膜重链和小蛋白β2-微球蛋白（β 2 m）的二聚体，结合内质网中由细胞蛋白质胞质周转产生的肽。在病毒感染的细胞中，这些肽可以包括衍生自病毒蛋白的那些。然后肽-MHC-I复合物通过分泌途径运输，并展示在细胞表面，其中那些含有病毒肽的复合物可以被杀死感染细胞的CD 8 + T淋巴细胞检测到。许多病毒通过编码下调MHC-I表达以避免CD 8 + T细胞识别的基因来增强其体内存活。在这里，我们报告了由SARS-CoV-2编码的两种辅助蛋白，SARS-CoV-2是正在进行的COVID-19大流行的病原体，使用不同的机制下调MHC-I的表达。首先，ORF 3a是一种病毒孔蛋白，通过分泌途径减少蛋白质（包括MHC-I）的全球运输。第二个是ORF 7a，与MHC-I重链特异性相互作用，作为β 2 m的分子模拟物抑制其缔合。这减慢了正确组装的MHC-I分子从内质网的退出。我们证明ORF 7a减少了人MHC-I等位基因HLA-A*02：01的抗原呈递。因此，ORF 3a和ORF 7a均在分泌途径中后分泌作用以降低表面MHC-I表达，其中ORF 7a表现出允许SARS-CoV-2免疫逃避的特异性机制。
Viruses may downregulate MHC class I expression on infected cells to avoid elimination by cytotoxic T cells. We report that the accessory proteins ORF7a and ORF3a of SARS-CoV-2 mediate this function and delineate the two distinct mechanisms involved. While ORF3a inhibits global protein trafficking to the cell surface, ORF7a acts specifically on MHC-I by competing with β2m for binding to the MHC-I heavy chain. This is the first account of molecular mimicry of β2m as a viral mechanism of MHC-I downregulation to facilitate immune evasion. Major histocompatibility complex class I (MHC-I) molecules, which are dimers of a glycosylated polymorphic transmembrane heavy chain and the small-protein β2-microglobulin (β2m), bind peptides in the endoplasmic reticulum that are generated by the cytosolic turnover of cellular proteins. In virus-infected cells, these peptides may include those derived from viral proteins. Peptide-MHC-I complexes then traffic through the secretory pathway and are displayed at the cell surface where those containing viral peptides can be detected by CD8+ T lymphocytes that kill infected cells. Many viruses enhance their in vivo survival by encoding genes that down-regulate MHC-I expression to avoid CD8+ T cell recognition. Here, we report that two accessory proteins encoded by SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic, down-regulate MHC-I expression using distinct mechanisms. First, ORF3a, a viroporin, reduces the global trafficking of proteins, including MHC-I, through the secretory pathway. The second, ORF7a, interacts specifically with the MHC-I heavy chain, acting as a molecular mimic of β2m to inhibit its association. This slows the exit of properly assembled MHC-I molecules from the endoplasmic reticulum. We demonstrate that ORF7a reduces antigen presentation by the human MHC-I allele HLA-A*02:01. Thus, both ORF3a and ORF7a act post-translationally in the secretory pathway to lower surface MHC-I expression, with ORF7a exhibiting a specific mechanism that allows immune evasion by SARS-CoV-2.
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影响因子：
8.8
作者：
Dittmar M;Lee JS;Whig K;Segrist E;Li M;Kamalia B;Castellana L;Ayyanathan K;Cardenas-Diaz FL;Morrisey EE;Truitt R;Yang W;Jurado K;Samby K;Ramage H;Schultz DC;Cherry S
通讯作者：
Cherry S
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
DOI：
10.1073/pnas.2101161118
发表时间：
2021-06-15
影响因子：
11.1
作者：
Hsu JC;Laurent-Rolle M;Pawlak JB;Wilen CB;Cresswell P
通讯作者：
Cresswell P
影响因子：
8.4
作者：
Chen W;Smeekens JM;Wu R
通讯作者：
Wu R
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.