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

Area of Science:

• Virology
• Cell Biology
• Structural Biology

Background:

• SARS-CoV-2 exhibits broad tissue tropism, influenced by host cell entry receptor availability.
• Angiotensin-converting enzyme 2 (ACE2) is the primary known receptor for SARS-CoV-2 entry.
• Understanding alternative entry pathways is crucial for combating viral spread.

Purpose of the Study:

• To identify alternative cellular receptors for SARS-CoV-2 entry beyond ACE2.
• To elucidate the mechanism of SARS-CoV-2 interaction with TMEM106B.
• To investigate the role of TMEM106B in viral fusion and infection.

Main Methods:

• Utilized X-ray crystallography and cryogenic electron microscopy (cryo-EM) to determine structural interactions.
• Employed hydrogen-deuterium exchange mass spectrometry (HDX-MS) to analyze protein dynamics.
• Tested the efficacy of TMEM106B-specific monoclonal antibodies in blocking viral infection.

Main Results:

• Identified TMEM106B, a lysosomal transmembrane protein, as an alternative SARS-CoV-2 entry receptor in ACE2-negative cells.
• Demonstrated that a specific Spike mutation (E484D) enhances TMEM106B binding and viral entry.
• Showed that TMEM106B-specific antibodies inhibit SARS-CoV-2 infection.
• Structural analysis revealed the TMEM106B luminal domain interacts with the SARS-CoV-2 Spike receptor-binding motif.
• Observed that TMEM106B promotes spike-mediated syncytium formation, indicating a role in viral fusion.

Conclusions:

• TMEM106B mediates ACE2-independent SARS-CoV-2 entry.
• Cooperative interactions between heparan sulfate and TMEM106B facilitate SARS-CoV-2 infection.
• TMEM106B represents a novel target for antiviral strategies against SARS-CoV-2.