作者
Jim Baggen,Maarten Jacquemyn,Leentje Persoons,Els Vanstreels,V.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
摘要
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.