ADAM10 and ADAM17 Promote SARS-CoV-2 Cell Entry and Spike Protein-mediated Lung Cell Fusion

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2022 May 9

PMID 35527514

Authors

Georg Jocher

Vincent Grass

Sarah K Tschirner

Lydia Riepler

Stephan Breimann

Tugberk Kaya

Madlen Oelsner

M Sabri Hamad

Laura I Hofmann

Carl P Blobel

Carsten B Schmidt-Weber

Ozgun Gokce

Constanze A Jakwerth

Jakob Trimpert

Janine Kimpel

Andreas Pichlmair

Stefan F Lichtenthaler

Affiliations

Soon will be listed here.

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.

Citing Articles

Oral SARS-CoV-2 Infection and Risk for Long Covid.

Schwartz J, Capistrano K, Hussein H, Hafedi A, Shukla D, Naqvi A Rev Med Virol. 2025; 35(2):e70029.

PMID: 40074704 PMC: 11903386. DOI: 10.1002/rmv.70029.

Analysis of Biomarker Levels in Nasopharyngeal Swabs, Serum, and Saliva Across Different Health Conditions.

Pencheva M, Manchorova-Veleva N, Baruh D, Rusinov G, Vangelov L Life (Basel). 2025; 15(2).

PMID: 40003732 PMC: 11857456. DOI: 10.3390/life15020324.

Activity of Various Cathepsin Proteases and Enrichment of Klotho Protein in the Urine and Urinary Extracellular Vesicles After SARS-CoV-2 Infection.

Bala N, Rafay R, Glover S, Alli A Viruses. 2025; 17(1).

PMID: 39861814 PMC: 11768607. DOI: 10.3390/v17010025.

Phenotypic evolution of SARS-CoV-2 spike during the COVID-19 pandemic.

Furnon W, Cowton V, De Lorenzo G, Orton R, Herder V, Cantoni D Nat Microbiol. 2025; 10(1):77-93.

PMID: 39753670 PMC: 11726466. DOI: 10.1038/s41564-024-01878-5.

Unraveling the SARS-CoV-2 spike protein long-term effect on neuro-PASC.

Menezes F, da Fonseca Palmeira J, Oliveira J, Arganaraz G, Soares C, Nobrega O Front Cell Neurosci. 2025; 18:1481963.

PMID: 39744674 PMC: 11688492. DOI: 10.3389/fncel.2024.1481963.

References

Dittmar M, Lee J, Whig K, Segrist E, Li M, Kamalia B . Drug repurposing screens reveal cell-type-specific entry pathways and FDA-approved drugs active against SARS-Cov-2. Cell Rep. 2021; 35(1):108959. PMC: 7985926. DOI: 10.1016/j.celrep.2021.108959. View

Houri N, Huang K, Nalbantoglu J . The Coxsackievirus and Adenovirus Receptor (CAR) undergoes ectodomain shedding and regulated intramembrane proteolysis (RIP). PLoS One. 2013; 8(8):e73296. PMC: 3756012. DOI: 10.1371/journal.pone.0073296. View

Zissler U, Jakwerth C, Guerth F, Pechtold L, Aguilar-Pimentel J, Dietz K . Early IL-10 producing B-cells and coinciding Th/Tr17 shifts during three year grass-pollen AIT. EBioMedicine. 2018; 36:475-488. PMC: 6197437. DOI: 10.1016/j.ebiom.2018.09.016. View

Zissler U, Chaker A, Effner R, Ulrich M, Guerth F, Piontek G . Interleukin-4 and interferon-γ orchestrate an epithelial polarization in the airways. Mucosal Immunol. 2015; 9(4):917-26. DOI: 10.1038/mi.2015.110. View

Moss M, Sklair-Tavron L, Nudelman R . Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Clin Pract Rheumatol. 2008; 4(6):300-9. DOI: 10.1038/ncprheum0797. View

Buxbaum J, Liu K, Luo Y, Slack J, Stocking K, Peschon J . Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem. 1998; 273(43):27765-7. DOI: 10.1074/jbc.273.43.27765. View

Glowacka I, Bertram S, Herzog P, Pfefferle S, Steffen I, Muench M . Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63. J Virol. 2009; 84(2):1198-205. PMC: 2798380. DOI: 10.1128/JVI.01248-09. View

Le Gall S, Bobe P, Reiss K, Horiuchi K, Niu X, Lundell D . ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor alpha, L-selectin, and tumor necrosis factor alpha. Mol Biol Cell. 2009; 20(6):1785-94. PMC: 2655247. DOI: 10.1091/mbc.e08-11-1135. View

Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798):270-273. PMC: 7095418. DOI: 10.1038/s41586-020-2012-7. View

10.

Calligaris M, Cuffaro D, Bonelli S, Spano D, Rossello A, Nuti E . Strategies to Target ADAM17 in Disease: From its Discovery to the iRhom Revolution. Molecules. 2021; 26(4). PMC: 7916773. DOI: 10.3390/molecules26040944. View

11.

Black R, Rauch C, Kozlosky C, Peschon J, Slack J, Wolfson M . A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature. 1997; 385(6618):729-33. DOI: 10.1038/385729a0. View

12.

Bussani R, Schneider E, Zentilin L, Collesi C, Ali H, Braga L . Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of advanced COVID-19 pathology. EBioMedicine. 2020; 61:103104. PMC: 7677597. DOI: 10.1016/j.ebiom.2020.103104. View

13.

Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pohlmann S . TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol. 2013; 88(2):1293-307. PMC: 3911672. DOI: 10.1128/JVI.02202-13. View

14.

Lambert D, Yarski M, Warner F, Thornhill P, Parkin E, Smith A . Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem. 2005; 280(34):30113-9. PMC: 8062222. DOI: 10.1074/jbc.M505111200. View

15.

Qian M, Bai S, Brogdon B, Wu J, Liu R, Covington M . Pharmacokinetics and pharmacodynamics of DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)), a potent and selective inhibitor of tumor necrosis factor alpha-converting enzyme.... Drug Metab Dispos. 2007; 35(10):1916-25. DOI: 10.1124/dmd.107.015933. View

16.

Romi E, Gokhman I, Wong E, Antonovsky N, Ludwig A, Sagi I . ADAM metalloproteases promote a developmental switch in responsiveness to the axonal repellant Sema3A. Nat Commun. 2014; 5:4058. DOI: 10.1038/ncomms5058. View

17.

Hoffmann M, Kleine-Weber H, Pohlmann S . A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells. Mol Cell. 2020; 78(4):779-784.e5. PMC: 7194065. DOI: 10.1016/j.molcel.2020.04.022. View

18.

Moss M, Jin S, Milla M, Bickett D, Burkhart W, Carter H . Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature. 1997; 385(6618):733-6. DOI: 10.1038/385733a0. View

19.

Han X, Zhou Z, Fei L, Sun H, Wang R, Chen Y . Construction of a human cell landscape at single-cell level. Nature. 2020; 581(7808):303-309. DOI: 10.1038/s41586-020-2157-4. View

20.

Kuhn P, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart J . ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J. 2010; 29(17):3020-32. PMC: 2944055. DOI: 10.1038/emboj.2010.167. View