TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry

SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, a lysosomal transmembrane protein, can serve as an alternative receptor for SARS-CoV-2 entry into angiotensin-converting enzyme 2 (...

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Veröffentlicht in:Cell Jg. 186; H. 16; S. 3427
Hauptverfasser: Baggen, Jim, Jacquemyn, Maarten, Persoons, Leentje, Vanstreels, Els, Pye, Valerie E, Wrobel, Antoni G, Calvaresi, Valeria, Martin, Stephen R, Roustan, Chloë, Cronin, Nora B, Reading, Eamonn, Thibaut, Hendrik Jan, Vercruysse, Thomas, Maes, Piet, De Smet, Frederik, Yee, Angie, Nivitchanyong, Toey, Roell, Marina, Franco-Hernandez, Natalia, Rhinn, Herve, Mamchak, Alusha Andre, Ah Young-Chapon, Maxime, Brown, Eric, Cherepanov, Peter, Daelemans, Dirk
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 03.08.2023
Schlagworte:
Angiotensin-Converting Enzyme 2 - metabolism
COVID-19
Humans
Membrane Proteins - metabolism
Nerve Tissue Proteins - metabolism
Protein Binding
Receptors, Virus - metabolism
SARS-CoV-2 - metabolism
Virus Internalization
SARS-CoV-2
TMEM106B crystal structure
ACE2-independent entry
antibody neutralization
TMEM106B
coronavirus
cryo-EM
entry receptor
ISSN:1097-4172, 1097-4172
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Zusammenfassung:SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, a lysosomal transmembrane protein, can serve as an alternative receptor for SARS-CoV-2 entry into angiotensin-converting enzyme 2 (ACE2)-negative cells. Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked SARS-CoV-2 infection, demonstrating a role of TMEM106B in viral entry. Using X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show that the luminal domain (LD) of TMEM106B engages the receptor-binding motif of SARS-CoV-2 spike. Finally, we show that TMEM106B promotes spike-mediated syncytium formation, suggesting a role of TMEM106B in viral fusion. Together, our findings identify an ACE2-independent SARS-CoV-2 infection mechanism that involves cooperative interactions with the receptors heparan sulfate and TMEM106B.
Bibliographie:ObjectType-Article-1
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2023.06.005