| First Author | Baggen J | Year | 2023 |
| Journal | Cell | Volume | 186 |
| Issue | 16 | Pages | 3427-3442.e22 |
| PubMed ID | 37421949 | Mgi Jnum | J:347490 |
| Mgi Id | MGI:7518074 | Doi | 10.1016/j.cell.2023.06.005 |
| Citation | Baggen J, et al. (2023) TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry. Cell 186(16):3427-3442.e22 |
| abstractText | 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. |
