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The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection

The Journal of biological chemistry, 2021-01, Vol.296, p.100759, Article 100759 [Peer Reviewed Journal]

2021 The Authors ;Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved. ;2021 The Authors 2021 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1016/j.jbc.2021.100759 ;PMID: 33965375

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  • Title:
    The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection
  • Author: Carlos, Anthony J. ; Ha, Dat P. ; Yeh, Da-Wei ; Van Krieken, Richard ; Tseng, Chun-Chih ; Zhang, Pu ; Gill, Parkash ; Machida, Keigo ; Lee, Amy S.
  • Subjects: Accelerated Communication ; ACE2 ; antibody ; GRP78 ; SARS-CoV-2 ; Spike protein
  • Is Part Of: The Journal of biological chemistry, 2021-01, Vol.296, p.100759, Article 100759
  • Description: 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.
  • Publisher: United States: Elsevier Inc
  • Language: English
  • Identifier: ISSN: 0021-9258
    EISSN: 1083-351X
    DOI: 10.1016/j.jbc.2021.100759
    PMID: 33965375
  • Source: PubMed Central
    Alma/SFX Local Collection
    DOAJ Directory of Open Access Journals
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