SARS-CoV-2 ORF8 Products

SARS-CoV-2 Open Reading Frame 8 (ORF8) is one of the nine downstream accessory protein open reading frames of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19 (1). SARS-CoV-2 ORF8 is 121 amino acids (aa) in length with a theoretical molecular weight of 13.8 kDa (2, 3). One particular difference between SARS-CoV-2 and SARS-CoV is that SARS-CoV-2 has one ORF8 protein, while SARS-CoV has two ORF8 proteins (ORF8a and ORF8b) (3). The aa sequence alignment of SARS-CoV-2's ORF8 has 31.7% sequence identity and 70.7% sequence similarity with SARS-CoV ORF8a (3). Furthermore, SARS-CoV-2 ORF8 has a 40.5% sequence identity and 66.7% sequence similarity is with SARS-CoV ORF8b (3). Despite this low sequence identity and similarity, the ORF8 structure and function appears to be well conserved (4). Both ORF8 proteins appear to be localized to the ER and have an N-terminal hydrophobic region, a conserved glycosylation site, and cysteine residues capable of forming disulfide bonds (4).

Studies have revealed that SARS-CoV-2 ORF8 has a role in host immune suppression during viral infection as it is an inhibitor of the type I interferon pathway (4, 5). Specifically, ORF8 has been shown to have antagonistic properties on interferon-beta (IFN-beta), the NF-kappabeta-responsive promoter, and the interferon-stimulated response element (ISRE) (4,5). Additionally, ORF8 colocalizes with the ER and lysosomal proteins Calnexin and LAMP1, playing a role in major histocompatibility complex class I (MHC-I) downregulation and degradation (4, 6). These results suggest that inhibiting ORF8 may be a potential approach for improving immune surveillance and more quickly eliminating SARS-CoV-2 infection (4-6).

References

1. Michel, C. J., Mayenr, C., Poch, O., & Thompson, J. D. (2020). Characterization of accessory genes in coronavirus genomes. Virology journal. https://doi.org/10.1186/s12985-020-01402-1

2. UniProt (P0DTC8)

3. Yoshimoto F. K. (2020). The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the Cause of COVID-19. The protein journal. https://doi.org/10.1007/s10930-020-09901-4

4. Mohammad, S., Bouchama, A., Mohammad Alharbi, B., Rashid, M., Saleem Khatlani, T., Gaber, N. S., & Malik, S. S. (2020). SARS-CoV-2 ORF8 and SARS-CoV ORF8ab: Genomic Divergence and Functional Convergence. Pathogens (Basel, Switzerland). https://doi.org/10.3390/pathogens9090677

5. Li, J. Y., Liao, C. H., Wang, Q., Tan, Y. J., Luo, R., Qiu, Y., & Ge, X. Y. (2020). The ORF6, ORF8 and nucleocapsid proteins of SARS-CoV-2 inhibit type I interferon signaling pathway. Virus research. https://doi.org/10.1016/j.virusres.2020.198074

6. Zhang Y., Zhang J., Chen Y., Luo B., Yuan Y., Huang F., Yang T., Yu F., Liu J., Liu B., et al. (2020). The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I. bioRxiv. https://doi.org/10.1101/2020.05.24.111823.