TMEM106B is a Receptor Mediating ACE2-independent SARS-CoV-2 Cell Entry

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2023 Jul 8

PMID 37421949

Authors

Jim Baggen

Maarten Jacquemyn

Leentje Persoons

Els Vanstreels

Valerie E Pye

Antoni G Wrobel

Valeria Calvaresi

Stephen R Martin

Chloe Roustan

Nora B Cronin

Eamonn Reading

Hendrik Jan Thibaut

Thomas Vercruysse

Piet Maes

Frederik De Smet

Angie Yee

Toey Nivitchanyong

Marina Roell

Natalia Franco-Hernandez

Herve Rhinn

Alusha Andre Mamchak

Maxime Ah Young-Chapon

Eric Brown

Peter Cherepanov

Dirk Daelemans

Affiliations

Soon will be listed here.

Abstract

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.

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