TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry

Baggen, Jim; Jacquemyn, Maarten; Persoons, Leentje; Vanstreels, Els; Pye, Valerie E; Wrobel, Antoni G; Calvaresi, Valeria; Martin, Stephen R; Roustan, Chloe; Cronin, Nora B; Reading, Eamonn; Thibaut, Hendrik Jan; Vercruysse, Thomas; Maes, Piet; Smet, Frederik De; Yee, Angie; Nivitchanyong, Toey; Roell, Marina; Franco-Hernandez, Natalia; Rhinn, Herve; Mamchak, Alusha Andre; Young-Chapon, Maxime Ah; Brown, Eric; Cherepanov, Peter; Daelemans, Dirk

doi:10.1016/j.cell.2023.06.005

TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry

Author:

Baggen, Jim

Jacquemyn, Maarten ; Persoons, Leentje ; Vanstreels, Els ; Pye, Valerie E ; Wrobel, Antoni G ; Calvaresi, Valeria ; Martin, Stephen R ; Roustan, Chloe ; Cronin, Nora B ; Reading, Eamonn ; Thibaut, Hendrik Jan ; Vercruysse, Thomas ; Maes, Piet ; Smet, Frederik De ; Yee, Angie ; Nivitchanyong, Toey ; Roell, Marina ; Franco-Hernandez, Natalia ; Rhinn, Herve ; Mamchak, Alusha Andre ; Young-Chapon, Maxime Ah ; Brown, Eric ; Cherepanov, Peter ; Daelemans, Dirk

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, CRYO-EM STRUCTURE, FRONTOTEMPORAL LOBAR DEGENERATION, RISK-FACTOR, REAL-TIME, DEMENTIA, SPIKE, ORIENTATION, TOOLS, ACE2, ACE2-independent entry, SARS-CoV-2, TMEM106B, TMEM106B crystal structure, antibody neutralization, coronavirus, cryo-EM, entry receptor, Humans, COVID-19, Angiotensin-Converting Enzyme 2, Receptors, Virus, Virus Internalization, Protein Binding, Membrane Proteins, Nerve Tissue Proteins, G067423N#57350768, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 31 Biological sciences, 32 Biomedical and clinical sciences

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.