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

SARS-CoV-2, the virus responsible for COVID-19, has the ability to infect various tissues due to its broad tissue tropism, which is influenced by the presence of specific entry receptors on host cells. In this study, we unveil a significant finding that TMEM106B, a lysosomal transmembrane protein, can act as an alternative receptor for SARS-CoV-2 to enter cells that lack angiotensin-converting enzyme 2 (ACE2), a well-known receptor for the virus.

Through our investigations, we observed that a specific mutation in the spike protein, known as E484D, enhances the binding of SARS-CoV-2 to TMEM106B, thereby facilitating viral entry through this alternative pathway. Notably, we found that monoclonal antibodies targeting TMEM106B effectively blocked SARS-CoV-2 infection, providing evidence of TMEM106B's role in viral entry.

Employing advanced techniques such as X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), we discovered that the luminal domain (LD) of TMEM106B interacts with the receptor-binding motif of the SARS-CoV-2 spike protein.

Furthermore, our research indicates that TMEM106B contributes to spike-mediated syncytium formation, suggesting its involvement in viral fusion, which is a crucial step in the infection process.

In conclusion, our findings shed light on a novel mechanism of SARS-CoV-2 infection that operates independently of ACE2 and involves cooperative interactions with heparan sulfate and TMEM106B receptors. This discovery deepens our understanding of the virus's pathogenesis and potential therapeutic targets for combating COVID-19.