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

Cell. 2023 Aug 3;186(16):3427-3442.e22. doi: 10.1016/j.cell.2023.06.005. Epub 2023 Jul 7.


SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, a lysosomal transmembrane protein, can serve as an alternative receptor for SARS-CoV-2 entry into angiotensin-converting enzyme 2 (ACE2)-negative cells. Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked SARS-CoV-2 infection, demonstrating a role of TMEM106B in viral entry. Using X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show that the luminal domain (LD) of TMEM106B engages the receptor-binding motif of SARS-CoV-2 spike. Finally, we show that TMEM106B promotes spike-mediated syncytium formation, suggesting a role of TMEM106B in viral fusion. Together, our findings identify an ACE2-independent SARS-CoV-2 infection mechanism that involves cooperative interactions with the receptors heparan sulfate and TMEM106B.

Keywords: ACE2-independent entry; SARS-CoV-2; TMEM106B; TMEM106B crystal structure; antibody neutralization; coronavirus; cryo-EM; entry receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / metabolism
  • COVID-19*
  • Humans
  • Membrane Proteins / metabolism
  • Nerve Tissue Proteins / metabolism
  • Protein Binding
  • Receptors, Virus / metabolism
  • SARS-CoV-2* / metabolism
  • Virus Internalization


  • Angiotensin-Converting Enzyme 2
  • Receptors, Virus
  • TMEM106B protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins