biostudies-literatureUnknown54Liu PThe 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 revRedox biology102388https://www.ebi.ac.uk/biostudies/studies/S-EPMC9239706biostudies-literatureSARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases.PMC9239706Cheng FHu JZhang HLiu PWang XWang CCSun YWang JYang FZhao HWang LfalseSARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases.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 rev2022-01-01T00:00:00Z2022 Aug2026-05-27T19:24:33.649Z2022-07-07T22:58:33.899ZS-EPMC92397063579243810.1016/j.redox.2022.102388