The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 global pandemic, utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) for viral entry. However, other host factors might also play important roles in SARS-CoV-2 infection, providing new directions for antiviral treatments. GRP78 is a stress-inducible chaperone ... important for entry and infectivity for many viruses. Recent molecular docking analyses revealed putative interaction between GRP78 and the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (SARS-2-S). Here we report that GRP78 can form a complex with SARS-2-S and ACE2 on the surface and at the perinuclear region typical of the endoplasmic reticulum in VeroE6-ACE2 cells and that the substrate-binding domain of GRP78 is critical for this interaction. In vitro binding studies further confirmed that GRP78 can directly bind to the RBD of SARS-2-S and ACE2. To investigate the role of GRP78 in this complex, we knocked down GRP78 in VeroE6-ACE2 cells. Loss of GRP78 markedly reduced cell surface ACE2 expression and led to activation of markers of the unfolded protein response. Treatment of lung epithelial cells with a humanized monoclonal antibody (hMAb159) selected for its safe clinical profile in preclinical models depleted cell surface GRP78 and reduced cell surface ACE2 expression, as well as SARS-2-S-driven viral entry and SARS-CoV-2 infection in vitro. Our data suggest that GRP78 is an important host auxiliary factor for SARS-CoV-2 entry and infection and a potential target to combat this novel pathogen and other viruses that utilize GRP78 in combination therapy.
Mesh Terms:
Angiotensin-Converting Enzyme 2, Animals, Antibodies, Monoclonal, Binding Sites, Chlorocebus aethiops, Endoplasmic Reticulum, Endoplasmic Reticulum Chaperone BiP, Gene Expression Regulation, Heat-Shock Proteins, Host-Pathogen Interactions, Humans, Mutation, Protein Binding, Protein Domains, Protein Multimerization, RNA, Small Interfering, SARS-CoV-2, Signal Transduction, Spike Glycoprotein, Coronavirus, Unfolded Protein Response, Vero Cells, Virus Internalization
Angiotensin-Converting Enzyme 2, Animals, Antibodies, Monoclonal, Binding Sites, Chlorocebus aethiops, Endoplasmic Reticulum, Endoplasmic Reticulum Chaperone BiP, Gene Expression Regulation, Heat-Shock Proteins, Host-Pathogen Interactions, Humans, Mutation, Protein Binding, Protein Domains, Protein Multimerization, RNA, Small Interfering, SARS-CoV-2, Signal Transduction, Spike Glycoprotein, Coronavirus, Unfolded Protein Response, Vero Cells, Virus Internalization
J Biol Chem
Date: May. 10, 2021
PubMed ID: 33965375
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