Middle East respiratory syndrome coronavirus and bat coronavirus HKU9 both can utilize GRP78 for attachment onto host cells

Abstract

Coronavirus tropism is predominantly determined by the interaction between coronavirus spikes and the host receptors. In this regard, coronaviruses have evolved a complicated receptor-recognition system through their spike proteins. Spikes from highly related coronaviruses can recognize distinct receptors, whereas spikes of distant coronaviruses can employ the same cell-surface molecule for entry. Moreover, coronavirus spikes can recognize a broad range of cell-surface molecules in addition to the receptors and thereby can augment coronavirus attachment or entry. The receptor of Middle East respiratory syndrome coronavirus (MERS-CoV) is dipeptidyl peptidase 4 (DPP4). In this study, we identified membrane-associated 78-kDa glucose-regulated protein (GRP78) as an additional binding target of the MERS-CoV spike. Further analyses indicated that GRP78 could not independently render nonpermissive cells susceptible to MERS-CoV infection but could facilitate MERS-CoV entry into permissive cells by augmenting virus attachment. More importantly, by exploring potential interactions between GRP78 and spikes of other coronaviruses, we discovered that the highly conserved human GRP78 could interact with the spike protein of bat coronavirus HKU9 (bCoV-HKU9) and facilitate its attachment to the host cell surface. Taken together, our study has identified GRP78 as a host factor that can interact with the spike proteins of two , the lineage C MERS-CoV and the lineage D bCoV-HKU9. The capacity of GRP78 to facilitate surface attachment of both a human coronavirus and a phylogenetically related bat coronavirus exemplifies the need for continuous surveillance of the evolution of animal coronaviruses to monitor their potential for human adaptations.

COVID-19 spike-host cell receptor GRP78 binding site prediction

“…The predicted binding site of the Spike protein to GRP7 found in this study is in good agreement with studies that identified the spike receptor-binding domain using antibodies 23,41 .…”

“…After model validation, molecular docking was performed to test its binding affinity against GRP78. We hypothesized that GRP78 binds to COVID-19, as it happens in the case of the MERS-CoV coronavirus 23 , and we tried to predict the binding site using the similarity between Pep42 and the COVID-19 Spike protein 14 . Four regions of the spike were predicted to be the binding site to GRP78 based on sequence and structural similarity.…”

GRP78: A cell's response to stress

“…They are classified into alpha-, beta-, gamma-, and delta coronaviruses [64]. One of the viruses belonging to betacoronaviruses is Middle East Respiratory Syndrome Coronavirus (MERS-CoV) which causes severe lower respiratory tract infection with a high mortality rate reaching 35% [64,65]. The MERS-CoV spike protein utilizes dipeptidyl peptidase 4 (DPP4) as its functional receptor for host cell entry [66].…”

“…In addition to its functional receptor, MERS-CoV can recognize other molecules to facilitate their attachment and entry, for example, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), and tetraspanin CD9 are identified as a factor promoting the virus entry in permissive cells [67,68]. Recently GRP78 was recognized as an attachment factor for MERS-CoV spike protein that enhances the virus entry in the presence of DPP4 [65]. In addition to GRP78 role in the entrance of the virus, it has a role in the replication of MERS-CoV [65].…”

Nucleoside analogues for the treatment of coronavirus infections

“…The cause of an ongoing epidemic of Middle East respiratory syndrome, MERS-CoV was first identified in Saudi Arabia in 2012 and to date has caused more than 2374 cases in 27 countries with a fatality rate >34% [3,4]. The use of human host cell receptors by both human and bat CoVs supports predictions of significant risk for emergence of new potential pandemic zoonotic CoVs [5,6]. Notably, no vaccines or antiviral compounds are approved for prevention or treatment of human or potential zoonotic CoVs.…”