ORF8/ORF8a: a difference between SARS-CoV-2 and SARS-CoV.

To the Editor:

Recently in an editorial published as an “early view” paper in the European Respiratory Journal, Hartsell et al. [1] reported that ORF8a has a role in SARS-CoV-2 infection. In figure 1, it was stated that ORF7a, ORF8a and ORF9b locate within the mitochondria and can inhibit RIG1-MAVS (retinoic acid-inducible gene I-mitochondrial antiviral signalling protein)-dependent interferon signalling, enhance viral replication and disrupt mitochondrial function [1], although based on scientific evidence, SARS-CoV-2 lacks ORF8a [2-4].

FIGURE 1

SARS-CoV-2 genome.

The genome of SARS-CoV-2 contains several accessory genes in the 3′-end of the genome that code nine accessory proteins (3a, 3b, 6, 7a, 7b, 8, 9b, 9c and 10), which are involved in SARS-CoV-2 infection (figure 1) [5]. SARS-CoV-2 ORF8 is a 121-amino acid protein which contains an N-terminal signal sequence which is followed by a predicted Ig-like fold. ORF8 protein has a signal sequence for import into the endoplasmic reticulum to interact with proteins of the host cell [6]. ORF8a is absent in SARS-CoV-2 because of a 29-nucleotide deletion that inactivates the formation of the ORF8ab tandem. ORF8 is split 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 characterise proteins of 39 and 84 amino acids, respectively [10]. ORF8a can induce apoptosis by a mitochondrion-dependent pathway [11].

In SARS-CoV-2, ORF8 has several functions during infection. ORF8 can disrupt IFN-I signalling when exogenously overexpressed in cells; it also downregulates levels of major histocompatibility complex (MHC) class Ι through direct binding [6], however this process is not observed for ORF8a and ORF8b. Furthermore, ORF8 degrades MHC-I via the autophagy pathway.

In conclusion, one of the differences between SARS-CoV-2 and SARS-CoV is ORF8/ORF8a, for which the SARS-CoV-2 genome encodes an intact ORF8; however, SARS-CoV encodes two proteins, ORF8a and ORF8b.

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