TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved..
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.
| Errataetall: |
CommentIn: Cell. 2023 Aug 3;186(16):3329-3331. - PMID 37541193 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:186 |
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| Enthalten in: |
Cell - 186(2023), 16 vom: 03. Aug., Seite 3427-3442.e22 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Baggen, Jim [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.08.2023 Date Revised 11.08.2023 published: Print-Electronic CommentIn: Cell. 2023 Aug 3;186(16):3329-3331. - PMID 37541193 Citation Status MEDLINE |
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| doi: |
10.1016/j.cell.2023.06.005 |
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| 500 | |a CommentIn: Cell. 2023 Aug 3;186(16):3329-3331. - PMID 37541193 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
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