Novel Omicron Variants Enhance Anchored Recognition of TMEM106B: A New Pathway for SARS-CoV-2 Cellular Invasion

The recent discovery that TMEM106B serves as a receptor mediating ACE2-independent SARS-CoV-2 entry into cells deserves attention, especially in the background of the frequent emergence of mutant strains. Here, the structure-dynamic features of this novel pathway are dissected deeply. Our investigation revealed that the large loop (RBD@471-491) could anchor TMEM106B, which was then firmly locked by another loop (RBD@444-451). The novel and widely disseminated Omicron variants (BA.2.86/EG.5.1) affect the anchoring recognition of proteins, with BA.2.86 being more likely to impact cells with limited or undetectable ACE2 expression. The large loop of the EG.5.1 variant captures TMEM106B poorly due to impaired electrostatic complementarity. Furthermore, we emphasize that antibody design against these two loops could enhance the protection of ACE2 low-expressing cells according to the alanine scanning mutagenesis of multiple antibodies. We hope this study will provide a novel perspective for the prevention and treatment against this new viral invasion pathway.