tetano
Editor, Senior Moderator
Cell
. 2023 Jul 3;S0092-8674(23)00645-1.
doi: 10.1016/j.cell.2023.06.005. Online ahead of print. TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry
Jim Baggen[SUP] 1 [/SUP], Maarten Jacquemyn[SUP] 2 [/SUP], Leentje Persoons[SUP] 2 [/SUP], Els Vanstreels[SUP] 2 [/SUP], Valerie E Pye[SUP] 3 [/SUP], Antoni G Wrobel[SUP] 4 [/SUP], Valeria Calvaresi[SUP] 5 [/SUP], Stephen R Martin[SUP] 4 [/SUP], Chloë Roustan[SUP] 6 [/SUP], Nora B Cronin[SUP] 7 [/SUP], Eamonn Reading[SUP] 5 [/SUP], Hendrik Jan Thibaut[SUP] 8 [/SUP], Thomas Vercruysse[SUP] 8 [/SUP], Piet Maes[SUP] 9 [/SUP], Frederik De Smet[SUP] 10 [/SUP], Angie Yee[SUP] 11 [/SUP], Toey Nivitchanyong[SUP] 11 [/SUP], Marina Roell[SUP] 11 [/SUP], Natalia Franco-Hernandez[SUP] 11 [/SUP], Herve Rhinn[SUP] 11 [/SUP], Alusha Andre Mamchak[SUP] 11 [/SUP], Maxime Ah Young-Chapon[SUP] 11 [/SUP], Eric Brown[SUP] 11 [/SUP], Peter Cherepanov[SUP] 12 [/SUP], Dirk Daelemans[SUP] 13 [/SUP]
Affiliations
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.
Keywords: ACE2-independent entry; SARS-CoV-2; TMEM106B; TMEM106B crystal structure; antibody neutralization; coronavirus; cryo-EM; entry receptor.
. 2023 Jul 3;S0092-8674(23)00645-1.
doi: 10.1016/j.cell.2023.06.005. Online ahead of print. TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry
Jim Baggen[SUP] 1 [/SUP], Maarten Jacquemyn[SUP] 2 [/SUP], Leentje Persoons[SUP] 2 [/SUP], Els Vanstreels[SUP] 2 [/SUP], Valerie E Pye[SUP] 3 [/SUP], Antoni G Wrobel[SUP] 4 [/SUP], Valeria Calvaresi[SUP] 5 [/SUP], Stephen R Martin[SUP] 4 [/SUP], Chloë Roustan[SUP] 6 [/SUP], Nora B Cronin[SUP] 7 [/SUP], Eamonn Reading[SUP] 5 [/SUP], Hendrik Jan Thibaut[SUP] 8 [/SUP], Thomas Vercruysse[SUP] 8 [/SUP], Piet Maes[SUP] 9 [/SUP], Frederik De Smet[SUP] 10 [/SUP], Angie Yee[SUP] 11 [/SUP], Toey Nivitchanyong[SUP] 11 [/SUP], Marina Roell[SUP] 11 [/SUP], Natalia Franco-Hernandez[SUP] 11 [/SUP], Herve Rhinn[SUP] 11 [/SUP], Alusha Andre Mamchak[SUP] 11 [/SUP], Maxime Ah Young-Chapon[SUP] 11 [/SUP], Eric Brown[SUP] 11 [/SUP], Peter Cherepanov[SUP] 12 [/SUP], Dirk Daelemans[SUP] 13 [/SUP]
Affiliations
- PMID: 37421949
- DOI: 10.1016/j.cell.2023.06.005
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.
Keywords: ACE2-independent entry; SARS-CoV-2; TMEM106B; TMEM106B crystal structure; antibody neutralization; coronavirus; cryo-EM; entry receptor.