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 Betacoronaviruses, 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.
Highlights
Coronavirus tropism is predominantly determined by the interaction between coronavirus spikes and the host receptors
Our study has identified GRP78 as a host factor that can interact with the spike proteins of two Betacoronaviruses, the lineage C MERS-CoV and the lineage D bCoV-HKU9
The spike proteins of coronaviruses can recognize a broad range of cell-surface molecules, which serve to augment coronavirus attachment or entry
Summary
Coronavirus tropism is predominantly determined by the interaction between coronavirus spikes and the host receptors. Coronavirus spikes can recognize a broad range of cell-surface molecules in addition to the receptors and thereby can augment coronavirus attachment or entry. MERS-CoV and bCoV-HKU9 both utilize GRP78 for attachment navirus OC43 (HCoV-OC43), and human coronavirus HKU1 (HCoV-HKU1) predominantly cause mild and self-limiting upper respiratory tract infections [5, 6]. Among the six human coronaviruses, the Alphacoronavirus HCoV-229E spike binds aminopeptidase N [12], whereas the lineage C Betacoronavirus the MERS-CoV spike recognizes dipeptidyl peptidase 4 (DPP4) [13]. The protein receptors for the lineage A Betacoronavirus HCoV-OC43 and HCoV-HKU1 are currently unknown In addition to their designated receptors, coronavirus spikes are known to recognize a broad array of cell-surface molecules, which serve to facilitate the attachment or entry of the viruses. Tetraspanin CD9 was identified as a host cell- -surface factor that facilitated MERS-CoV entry by scaffolding host cell receptors and proteases [26]
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