Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) is an inefficient inducer of interferon (IFN) response. It expresses various proteins that effectively circumvent IFN production at different levels via distinct mechanisms. Through the construction of recombinant IBV expressing proteins 8a, 8b and 8ab encoded by SARS-CoV ORF8, we demonstrate that expression of 8b and 8ab enables the corresponding recombinant viruses to partially overcome the inhibitory actions of IFN activation to achieve higher replication efficiencies in cells. We also found that proteins 8b and 8ab could physically interact with IRF3. Overexpression of 8b and 8ab resulted in the reduction of poly (I:C)-induced IRF3 dimerization and inhibition of the IFN-β signaling pathway. This counteracting effect was partially mediated by protein 8b/8ab-induced degradation of IRF3 in a ubiquitin-proteasome-dependent manner. Taken together, we propose that SARS-CoV may exploit the unique functions of proteins 8b and 8ab as novel mechanisms to overcome the effect of IFN response during virus infection.

Origin and evolution of pathogenic coronaviruses

“…These data indicate that orf8 genes underwent adaptations during transmission from animals to humans during the SARS epidemic. A limited functional analysis suggested that the ORF8a protein is dispensable for SARS-CoV replication in Vero E6 cells but may have a role in modulating endoplasmic reticulum 20,[65][66][67][68][69] . Whether and how these adaptations were involved in SARS-CoV virulence are not fully clarified.…”

Post-Translational Modifications of Coronavirus Proteins: Roles and Function

“…However, whereas glycosylation at N81 stabilized protein 8ab and protected it from proteasomal degradation, protein 8b was highly unstable and underwent rapid proteasomal degradation [168]. The ubiquitinated 8b and 8ab may mediate rapid degradation of IRF3 and regulate host antiviral innate immunity [169].…”

Nonstructural proteins NS7b and NS8 are likely to be phylogenetically associated with evolution of 2019-nCoV

“…A study involving MERS-CoV described that ORF 8b strongly antagonizes the INF-beta (β) promoter and ORF4b and 8b significantly suppress IFN induction (Lee et al, 2019b). Accessory proteins 8b and 8ab of SARS-CoV can suppress the INF-β signaling pathway (and thus interferon production) by their participation in the ubiquitin-mediated rapid degradation of INF regulatory factor 3 (IRF3) (Wong et al, 2018). In contrast, when we focused on MERS-CoV from bats and camels, ORF 8b antagonized melanoma differentiation-associated protein 5-mediated nuclear factor kappa B (NF-κB) activation.…”