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ADAM10 and ADAM17 promote SARS‐CoV‐2 cell entry and spike protein‐mediated lung cell fusion
Author(s) -
Jocher Georg,
Grass Vincent,
Tschirner Sarah K,
Riepler Lydia,
Breimann Stephan,
Kaya Tuğberk,
Oelsner Madlen,
Hamad M Sabri,
Hofmann Laura I,
Blobel Carl P,
SchmidtWeber Carsten B,
Gokce Ozgun,
Jakwerth Constanze A,
Trimpert Jakob,
Kimpel Janine,
Pichlmair Andreas,
Lichtenthaler Stefan F
Publication year - 2022
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202154305
Subject(s) - covid-19 , spike (software development) , cell , coronavirus , biology , adam10 , virology , betacoronavirus , cell fusion , spike protein , microbiology and biotechnology , genetics , medicine , computer science , metalloproteinase , outbreak , disease , pathology , infectious disease (medical specialty) , matrix metalloproteinase , disintegrin , software engineering
The severe‐acute‐respiratory‐syndrome‐coronavirus‐2 (SARS‐CoV‐2) is the causative agent of COVID‐19, but host cell factors contributing to COVID‐19 pathogenesis remain only partly understood. We identify the host metalloprotease ADAM17 as a facilitator of SARS‐CoV‐2 cell entry and the metalloprotease ADAM10 as a host factor required for lung cell syncytia formation, a hallmark of COVID‐19 pathology. ADAM10 and ADAM17, which are broadly expressed in the human lung, cleave the SARS‐CoV‐2 spike protein (S) in vitro , indicating that ADAM10 and ADAM17 contribute to the priming of S, an essential step for viral entry and cell fusion. ADAM protease‐targeted inhibitors severely impair lung cell infection by the SARS‐CoV‐2 variants of concern alpha, beta, delta, and omicron and also reduce SARS‐CoV‐2 infection of primary human lung cells in a TMPRSS2 protease‐independent manner. Our study establishes ADAM10 and ADAM17 as host cell factors for viral entry and syncytia formation and defines both proteases as potential targets for antiviral drug development.