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TMEM106B protein can serve as an alternative receptor for SARS-CoV-2 entry into ACE2-negative host cells

Jul 9, 2023 | About the Virus

Two host-cell factors are important for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into many cell types: the angiotensin-converting enzyme 2 (ACE2) receptor which is bound by the spike (S)-protein, and transmembrane protease, serine 2 (TMPRSS2), which cleaves S-protein, allowing this binding to take place. In addition to ACE2, the SARS-CoV-2 S protein has been reported to engage other cell-surface factors proposed to serve as attachment factors promoting SARS-CoV-2 entry. In this study, a group of researchers led by Belgian scientists demonstrated that TMEM106B, a lysosomal transmembrane protein, can serve as an alternative receptor for SARS-CoV-2 entry into the ACE2-negative cells. In addition, they showed that TMEM106B directly engages the receptor-binding domain (RBD) of the SARS-CoV-2 S protein and promotes syncytium formation.

SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus. Its genome encodes four structural proteins, namely the spike (S), envelope (E), nucleocapsid (N), and membrane (M) proteins. The S protein appears to be a major pathogenic factor that contributes to the unique pathogenesis of SARS-CoV-2. The S protein plays three critical roles in facilitating host cell entry: it must bind ACE2, be proteolytically processed, and promote membrane fusion.

The S protein is a glycosylated homotrimer with each monomer composed of subunits S1 and S2, separated by host cell proteases. The S1 domain comprises the N-terminal domain (NTD), RBD with a receptor binding motif (RBM), and two C-terminal domains. The RBD in the S1 subunit recognizes human ACE2 and is responsible for attachment to host cells. ACE2 is highly expressed in the upper respiratory tract, and other human organs, such as the digestive tract, heart, kidney, and reproductive tissues.

Furin proteolytically processes S protein, resulting in cleaved forms of S1 and S2 subunits. One of the functional outcomes of the S1/S2 cleaved S protein is syncytium formation, where a SARS-CoV-2-infected cell can directly fuse with an adjacent cell. The S protein-mediated syncytia formation is expected to be highly cytopathic.

The lysosomal transmembrane protein TMEM106B is expressed in numerous cell types, with the highest levels found in the brain, heart, thyroid, adrenal, and testis. TMEM106B has been linked with brain aging, myelination disorders, and several neurodegenerative diseases, such as frontotemporal lobar degeneration, amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease.

About the study

To determine whether TMEM106B can serve as a receptor for SARS-CoV-2 entry into ACE2-negative cells, the scientists used a multimodal method that demonstrated an interaction of the luminal domain of TMEM106B with the RBM of the SARS-CoV-2 S1 protein. The affinity of the interaction between the S protein and TMEM106B was lower than the affinity of the S protein binding to ACE2. However, the affinity of the interaction between the S protein and TMEM106B was similar to the affinity of the S protein binding to neuropilin 1. The authors noted that ACE2 and TMEM106B cannot simultaneously bind the SARS-CoV-2 S protein, as demonstrated by a competition assay.

The S protein substitution E484D increased viral entry via the TMEM106B-dependent route. Some previous studies reported that E484D enabled the SARS-CoV-2 infection of ACE2-negative cell lines, but the underlying mechanism is unknown.

The results also showed that TMEM106B directly promoted syncytium formation mediated by the S protein.

Conclusion

This study found that SARS-CoV-2 can enter ACE2-deficient host cells through a TMEM106B-dependent entry mechanism. These findings show that TMEM106B and ACE2 support separate infection mechanisms, and explain the infection of cells with low or undetectable expression of ACE2. However, the mechanism by which TMEM106B promotes SARS-CoV-2 infection remains unclear.

This article was published in Cell.

Journal Reference

Baggen et al., TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry, Cell (2023).  https://doi.org/10.1016/j.cell.2023.06.005

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