key: cord-0763727-xncrrtla authors: Zandi, Milad title: ORF8/ORF8a: a difference between SARS-CoV-2 and SARS-CoV date: 2021-12-09 journal: Eur Respir J DOI: 10.1183/13993003.02818-2021 sha: e02e9cefe0d9fdf560140b0cc0e54738fd6b9312 doc_id: 763727 cord_uid: xncrrtla Recently in a published article in European respiratory journal, the authors reported ORF8a has a role in SARS-CoV-2 infection [1]. In figure 1, the authors stated ORF7a, ORF8a and ORF9b locate within the mitochondria and can inhibit RIG1- MAVS dependent interferon signaling, enhance viral replication and disrupt mitochondrial function [1], although based on scientific evidence, SARS-CoV-2 lacks ORF8a [2–4]. Recently in a published article in European respiratory journal, the authors reported ORF8a has a role in SARS-CoV-2 infection(1). In figure 1 , the authors stated ORF7a, ORF8a and ORF9b locate within the mitochondria and can inhibit RIG1-MAVS dependent interferon signaling, enhance viral replication and disrupt mitochondrial function(1), although based on scientific evidence, SARS-CoV-2 lacks ORF8a (2) (3) (4) . The genome of SARS-CoV-2 contains several accessory genes in the 3′-end of genome that codes nine accessory proteins (3a, 3b, 6, 7a, 7b, 8, 9b, 9c and 10) which are involved in SARS-CoV-2 infection(5) (Fig. 1 ). SARS-CoV-2 ORF8 is a 121-amino acid protein which contains an Nterminal signal sequence which followed by a predicted Ig-like fold. ORF8 protein has a signal sequence for import into ER to interact with proteins of host cell (6) . ORF8a is absent in SARS-CoV-2 because of a 29-nucleotide deletion that inactivates the formation ORF8ab tandem. ORF8 splitting into two separated ORFs (ORF8a and ORF8b) in SARS-CoV. An intact ORF8 is encoded by SARS-CoV-2 that shares the least homology among SARS-CoV-2 and SARS-CoV proteins (7) . SARS-CoV-2 encodes two viral proteins with ion channel activity (viroporin): 3a and E (8), but SARS-CoV encodes three: proteins 3a, E, and 8a (9) . In SARS-CoV, ORF8 gene encodes two proteins, ORF8a and ORF8b, which characterize proteins of 39 and 84 aa, respectively (10) . ORF8a can induce apoptosis by a mitochondrion-dependent pathway (11) . SARS-CoV-2's ORF8 has several function during infection. ORF8 can disrupt IFN-I signaling when exogenously overexpressed in cells, it also downregulates levels of MHC-1 through direct binding (6) , however this process is not observed for ORF8a and ORF8b, furthermore, ORF8 degrades MHC-1 via the autophagy pathway. In conclusion, one of the differences between SARS-CoV-2 and SARS-CoV is ORF8/ORF8a, which presented SARS-CoV-2's genome encodes an intact ORF8, however, SARS-CoV encodes two proteins, ORF8a and ORF8b. Conflict of interest: Milad Zandi declares no conflict of interest for this article Does acute and persistent metabolic dysregulation in COVID19 point to novel biomarkers and future therapeutic strategies? SARS-CoV-2: An overview of virus genetics, transmission, and immunopathogenesis Coronavirus biology and replication: implications for SARS-CoV-2 The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Ι An overview on the seven pathogenic human coronaviruses Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein ORF8a as a viroporin in SARS-CoV-2 infection? Cytokine & Growth Factor Reviews Cryo-EM structure of SARS-CoV-2 ORF3a in lipid nanodiscs Role of severe acute respiratory syndrome coronavirus viroporins E, 3a, and 8a in replication and pathogenesis SARS-CoV-2 ORF8 and SARS-CoV ORF8ab: genomic divergence and functional convergence Open reading frame 8a of the human severe acute respiratory syndrome coronavirus not only promotes viral replication but also induces apoptosis. The Journal of infectious diseases