SARS-CoV-2 ORF8 does not function in the nucleus as a histone mimic

Disruption of epigenetic regulation in host cells is a common evasion strategy used by viruses(Ozturkler and Kalkan 2021).Recently,Kee et al.(2022)reported that accessory protein ORF8 of SARS-CoV-2 can diffuse into the cell nucleus and mimic histone H3 through the ARKS motif,thereby interfering with H3 post-translational modifications(PTMs),disrupting gene transcription,and diminishing the antiviral response.These observations are surprising and unlikely because we and others have reported that SARS-CoV-2 ORF8 contains an N-terminal signal peptide for endoplasmic reticulum(ER)import(Flower et al.2021;Liu et al.2022),making it nearly impossible for it to wander into the nucleus.Instead,we showed that ORF8 protein accumulates in the ER lumen and escapes the degradation system by forming mixed disulfide complexes with ER-resident oxidoreductases,which subsequently activates the unfolded protein response(UPR)and remodels the ER to facilitate viral replication(Liu et al.2022).