SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases.
SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases.
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SARS-CoV-2 ORF8 通过与内质网氧化还原酶形成混合二硫化物来重塑内质网
DOI：
10.1016/j.redox.2022.102388
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发表时间：
2022-08
期刊：
影响因子：
11.4
通讯作者：
Wang, Lei
中科院分区：
文献类型：
--
作者：
Liu, Ping;Wang, Xi;Sun, Yiwei;Zhao, Hongyu;Cheng, Fang;Wang, Jifeng;Yang, Fuquan;Hu, Junjie;Zhang, Hong;Wang, Chih-Chen;Wang, Lei
严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）的复制机制与宿主细胞的内质网（ER）密切相关。激活未折叠蛋白反应（UPR）是冠状病毒劫持的一种策略，以促进其复制并抑制宿主先天免疫。在这里，我们发现SARS-CoV-2 ORF 8蛋白在ER中积累，并通过与ER氧化还原酶形成混合二硫键复合物而逃离降解系统。ORF 8通过靶向UPR的关键组分，诱导三条UPR通路的激活，重塑ER形态，加速蛋白运输。此外，小分子还原剂从混合二硫键复合物中释放ORF 8并促进其降解，从而减轻ER应激。我们的研究揭示了SARS-CoV-2 ORF 8逃避宿主细胞降解并调节ER重塑的独特机制。靶向ORF 8参与的混合二硫键复合物可能是减轻SARS-CoV-2诱导的ER应激及相关疾病的新策略。SARS-CoV-2 ORF 8蛋白通过形成混合二硫键复合物在ER中积累。两种关键的蛋白质二硫键异构酶PDI和ERp 44是ORF 8的主要靶点。ORF 8诱导ER应激，重塑ER并加速蛋白质运输。小分子还原剂促进ORF 8的降解并减轻ER应激。
The replication machinery of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is closely associated with the endoplasmic reticulum (ER) in host cells. Activation of the unfolded protein response (UPR) is a strategy hijacked by coronavirus to facilitate its replication and suppress host innate immunity. Here, we have found that SARS-CoV-2 ORF8 protein accumulates in the ER and escapes the degradation system by forming mixed disulfide complexes with ER oxidoreductases. ORF8 induces the activation of three UPR pathways through targeting key UPR components, remodels ER morphology and accelerates protein trafficking. Moreover, small molecule reducing agents release ORF8 from the mixed disulfide complexes and facilitate its degradation, therefore mitigate ER stress. Our study reveals a unique mechanism by which SARS-CoV-2 ORF8 escapes degradation by host cells and regulates ER reshaping. Targeting ORF8-involved mixed disulfide complexes could be a new strategy to alleviate SARS-CoV-2 induced ER stress and related diseases. SARS-CoV-2 ORF8 protein accumulates in the ER through forming mixed disulfide complexes. Two key protein disulfide isomerases, PDI and ERp44, are main targets of ORF8. ORF8 induces ER stress, remodels the ER and accelerates protein trafficking. Small molecule reducing agents facilitates the degradation of ORF8 and mitigates ER stress.