TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry
Jim Baggen, Maarten Jacquemyn, Leentje Persoons, Els Vanstreels, Valerie E. Pye, Antoni G. Wrobel, Valeria Calvaresi, Stephen R. Martin, Chloë Roustan, Nora Cronin, Eamonn Reading, Hendrik Jan Thibaut, Thomas Vercruysse, Piet Maes, Frederik De Smet, Angie Yee, Toey Nivitchanyong, Marina K. Roell, Natalia Franco-Hernandez, Hervé Rhinn, Alusha A. Mamchak, Maxime Ah Young-Chapon, Eric D. Brown, Peter Cherepanov, Dirk Daelemans
Abstract
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.