tetano
Editor, Senior Moderator
EMBO Rep
. 2022 May 8;e54305.
doi: 10.15252/embr.202154305. Online ahead of print.
ADAM10 and ADAM17 promote SARS-CoV-2 cell entry and spike protein-mediated lung cell fusion
Georg Jocher[SUP] #[/SUP][SUP] 1 2 [/SUP], Vincent Grass[SUP] #[/SUP][SUP] 3 [/SUP], Sarah K Tschirner[SUP] 1 2 [/SUP], Lydia Riepler[SUP] 4 [/SUP], Stephan Breimann[SUP] 1 2 5 [/SUP], Tuğberk Kaya[SUP] 1 6 7 [/SUP], Madlen Oelsner[SUP] 8 [/SUP], M Sabri Hamad[SUP] 3 [/SUP], Laura I Hofmann[SUP] 1 2 [/SUP], Carl P Blobel[SUP] 9 10 [/SUP], Carsten B Schmidt-Weber[SUP] 8 [/SUP], Ozgun Gokce[SUP] 7 11 [/SUP], Constanze A Jakwerth[SUP] 8 [/SUP], Jakob Trimpert[SUP] 12 [/SUP], Janine Kimpel[SUP] 4 [/SUP], Andreas Pichlmair[SUP] #[/SUP][SUP] 3 13 [/SUP], Stefan F Lichtenthaler[SUP] #[/SUP][SUP] 1 2 11 [/SUP]
Affiliations
Abstract
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.
Keywords: A549; DPC-333; apratastat; ectodomain shedding; syncytia formation.
. 2022 May 8;e54305.
doi: 10.15252/embr.202154305. Online ahead of print.
ADAM10 and ADAM17 promote SARS-CoV-2 cell entry and spike protein-mediated lung cell fusion
Georg Jocher[SUP] #[/SUP][SUP] 1 2 [/SUP], Vincent Grass[SUP] #[/SUP][SUP] 3 [/SUP], Sarah K Tschirner[SUP] 1 2 [/SUP], Lydia Riepler[SUP] 4 [/SUP], Stephan Breimann[SUP] 1 2 5 [/SUP], Tuğberk Kaya[SUP] 1 6 7 [/SUP], Madlen Oelsner[SUP] 8 [/SUP], M Sabri Hamad[SUP] 3 [/SUP], Laura I Hofmann[SUP] 1 2 [/SUP], Carl P Blobel[SUP] 9 10 [/SUP], Carsten B Schmidt-Weber[SUP] 8 [/SUP], Ozgun Gokce[SUP] 7 11 [/SUP], Constanze A Jakwerth[SUP] 8 [/SUP], Jakob Trimpert[SUP] 12 [/SUP], Janine Kimpel[SUP] 4 [/SUP], Andreas Pichlmair[SUP] #[/SUP][SUP] 3 13 [/SUP], Stefan F Lichtenthaler[SUP] #[/SUP][SUP] 1 2 11 [/SUP]
Affiliations
- PMID: 35527514
- DOI: 10.15252/embr.202154305
Abstract
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.
Keywords: A549; DPC-333; apratastat; ectodomain shedding; syncytia formation.