TMEM106B mediates ACE2-independent replication of the SARS-CoV-2 S-E484D variant in airway-derived cell models

TMEM106B is required for ACE2-independent SARS-CoV-2 S-E484D infection in NCI-H522 and NCI-H661 airway-derived cells, with TMEM106B knockout completely abolishing infection.

• Why it matters: ACE2 is the main entry receptor, but an ACE2-independent route linked to heparan sulfates and Spike E484D remains incompletely defined, limiting understanding of variant-specific tropism.
• What they did: The study expanded airway-derived cell models supporting ACE2-independent, S-E484D-dependent entry and used TMEM106B knockout and ectopic TMEM106B CTD expression, plus Fc-TMEM106B-CTD binding and blocking assays.
• The result: S-E484D, but not other E484 substitutions, enabled TMEM106B utilization; Fc-TMEM106B-CTD bound VSV-SARS-CoV-2 SE484D with higher affinity than WT and blocked infection, and serial passaging identified V951A enhancing spread and fusogenicity.

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