Neuropilin-1 is a host factor for SARS-CoV-2 infection

James L Daly; Boris Simonetti; Katja Klein; Kai-En Chen; Maia Kavanagh Williamson; Carlos Antón-Plágaro; Deborah K Shoemark; Lorena Simón-Gracia; Michael Bauer; Reka Hollandi; Urs F Greber; Peter Horvath; Richard B Sessions; Ari Helenius; Julian A Hiscox; Tambet Teesalu; David A Matthews; Andrew D Davidson; Brett M Collins; Peter J Cullen; Yohei Yamauchi

doi:10.1126/science.abd3072

Neuropilin-1 is a host factor for SARS-CoV-2 infection

Science. 2020 Nov 13;370(6518):861-865. doi: 10.1126/science.abd3072. Epub 2020 Oct 20.

Authors

James L Daly^#¹, Boris Simonetti^#², Katja Klein^#³, Kai-En Chen^#⁴, Maia Kavanagh Williamson^#³, Carlos Antón-Plágaro^#¹, Deborah K Shoemark⁵, Lorena Simón-Gracia⁶, Michael Bauer⁷, Reka Hollandi⁸, Urs F Greber⁷, Peter Horvath^{8

9}, Richard B Sessions¹, Ari Helenius¹⁰, Julian A Hiscox^{11

12}, Tambet Teesalu⁶, David A Matthews³, Andrew D Davidson³, Brett M Collins⁴, Peter J Cullen², Yohei Yamauchi^{13

14}

Affiliations

¹ School of Biochemistry, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
² School of Biochemistry, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK. bs13866@bristol.ac.uk pete.cullen@bristol.ac.uk yohei.yamauchi@bristol.ac.uk.
³ School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
⁴ Institute for Molecular Bioscience, the University of Queensland, St. Lucia, QLD 4072, Australia.
⁵ School of Biochemistry and BrisSynBio Centre, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
⁶ Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
⁷ Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
⁸ Synthetic and Systems Biology Unit, Biological Research Centre (BRC), Szeged, Hungary.
⁹ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
¹⁰ Institute of Biochemistry, ETH Zurich, Zurich, Switzerland.
¹¹ Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
¹² Singapore Immunology Network, Agency for Science, Technology, and Research, 138648, Singapore.
¹³ School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK. bs13866@bristol.ac.uk pete.cullen@bristol.ac.uk yohei.yamauchi@bristol.ac.uk.
¹⁴ Division of Biological Science, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.

^# Contributed equally.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), uses the viral spike (S) protein for host cell attachment and entry. The host protease furin cleaves the full-length precursor S glycoprotein into two associated polypeptides: S1 and S2. Cleavage of S generates a polybasic Arg-Arg-Ala-Arg carboxyl-terminal sequence on S1, which conforms to a C-end rule (CendR) motif that binds to cell surface neuropilin-1 (NRP1) and NRP2 receptors. We used x-ray crystallography and biochemical approaches to show that the S1 CendR motif directly bound NRP1. Blocking this interaction by RNA interference or selective inhibitors reduced SARS-CoV-2 entry and infectivity in cell culture. NRP1 thus serves as a host factor for SARS-CoV-2 infection and may potentially provide a therapeutic target for COVID-19.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Motifs
Angiotensin-Converting Enzyme 2
Antibodies, Monoclonal / immunology
Antibodies, Monoclonal / metabolism
Betacoronavirus / physiology*
COVID-19
Caco-2 Cells
Coronavirus Infections / virology
Crystallography, X-Ray
Furin / metabolism
HeLa Cells
Humans
Mutagenesis, Site-Directed
Neuropilin-1 / antagonists & inhibitors
Neuropilin-1 / chemistry
Neuropilin-1 / genetics
Neuropilin-1 / metabolism*
Pandemics
Peptide Fragments / chemistry
Peptide Fragments / metabolism
Peptidyl-Dipeptidase A / genetics
Peptidyl-Dipeptidase A / metabolism
Pneumonia, Viral / virology
Protein Binding
Protein Interaction Domains and Motifs
RNA Interference
SARS-CoV-2
Spike Glycoprotein, Coronavirus / chemistry
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / metabolism*
Virus Internalization*

Substances

Antibodies, Monoclonal
NRP1 protein, human
Peptide Fragments
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2
Neuropilin-1
Peptidyl-Dipeptidase A
ACE2 protein, human
Angiotensin-Converting Enzyme 2
FURIN protein, human
Furin

Abstract

Publication types

MeSH terms

Substances

Grants and funding