SARS-CoV-2 protein ORF8 limits expression levels of Spike antigen and facilitates immune evasion of infected host cells.
SARS-CoV-2 protein ORF8 limits expression levels of Spike antigen and facilitates immune evasion of infected host cells.
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DOI：
10.1016/j.jbc.2023.104955
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发表时间：
2023-08
影响因子：
4.8
通讯作者：
Verdin, Eric
中科院分区：
文献类型：
--
作者：
Kim, Ik-Jung;Lee, Yong-ho;Khalid, Mir M.;Chen, Irene P.;Zhang, Yini;Ott, Melanie;Verdin, Eric
从COVID-19中恢复取决于宿主有效中和病毒粒子和受感染细胞的能力，这一过程主要由抗体介导的免疫驱动。然而，随着新出现的逃避刺靶抗体的变异，再次感染和突破感染越来越普遍。因此，需要全面表征严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）对抗抗体介导免疫的机制。在这里，我们报道ORF8是一种病毒编码的SARS-CoV-2因子，控制细胞刺突抗原水平。我们发现ORF8通过抑制宿主蛋白合成和在内质网保留Spike，降低细胞表面Spike水平和抗sars - cov -2抗体的识别来限制成熟Spike的可用性。在刺突可用性有限的情况下，我们发现ORF8限制了病毒组装过程中刺突的结合，降低了病毒粒子中的刺突水平。这些病毒粒子进入细胞后，在细胞表面留下更少的Spike分子，限制了抗体对受感染细胞的识别。基于这些发现，我们提出SARS-CoV-2变体可能采用orf8依赖策略，促进受感染细胞的免疫逃避以延长病毒生产。
Recovery from COVID-19 depends on the ability of the host to effectively neutralize virions and infected cells, a process largely driven by antibody-mediated immunity. However, with the newly emerging variants that evade Spike-targeting antibodies, re-infections and breakthrough infections are increasingly common. A full characterization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mechanisms counteracting antibody-mediated immunity is therefore needed. Here, we report that ORF8 is a virally encoded SARS-CoV-2 factor that controls cellular Spike antigen levels. We show that ORF8 limits the availability of mature Spike by inhibiting host protein synthesis and retaining Spike at the endoplasmic reticulum, reducing cell-surface Spike levels and recognition by anti-SARS-CoV-2 antibodies. In conditions of limited Spike availability, we found ORF8 restricts Spike incorporation during viral assembly, reducing Spike levels in virions. Cell entry of these virions then leaves fewer Spike molecules at the cell surface, limiting antibody recognition of infected cells. Based on these findings, we propose that SARS-CoV-2 variants may adopt an ORF8-dependent strategy that facilitates immune evasion of infected cells for extended viral production.
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