Endosomal fusion of pH-dependent enveloped viruses requires ion channel TRPM7

Catherine A. Doyle, Gregory W. Busey, Wesley H. Iobst, Volker Kiessling, Chloe Renken, Hansa Doppalapudi, Marta E. Stremska, Mohan C. Manjegowda, Mohd Arish, Weiming Wang, Shardul Naphade, Joel Kennedy, Louis-Marie Bloyet, Cassandra E. Thompson, Paul W. Rothlauf, Eric J. Stipes, Sean P. J. Whelan, Lukas K. Tamm, Alex J. B. Kreutzberger, Jie Sun and Bimal N. Desai ()
Additional contact information
Catherine A. Doyle: University of Virginia
Gregory W. Busey: University of Virginia
Wesley H. Iobst: University of Virginia
Volker Kiessling: University of Virginia
Chloe Renken: University of Virginia
Hansa Doppalapudi: University of Virginia
Marta E. Stremska: University of Virginia
Mohan C. Manjegowda: University of Virginia
Mohd Arish: University of Virginia
Weiming Wang: Harvard Medical School
Shardul Naphade: University of Virginia
Joel Kennedy: University of Virginia
Louis-Marie Bloyet: Washington University School of Medicine
Cassandra E. Thompson: Washington University School of Medicine
Paul W. Rothlauf: Washington University School of Medicine
Eric J. Stipes: University of Virginia
Sean P. J. Whelan: Washington University School of Medicine
Lukas K. Tamm: University of Virginia
Alex J. B. Kreutzberger: Harvard Medical School
Jie Sun: University of Virginia
Bimal N. Desai: University of Virginia

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract The majority of viruses classified as pandemic threats are enveloped viruses which enter the cell through receptor-mediated endocytosis and take advantage of endosomal acidification to activate their fusion machinery. Here we report that the endosomal fusion of low pH-requiring viruses is highly dependent on TRPM7, a widely expressed TRP channel that is located on the plasma membrane and in intracellular vesicles. Using several viral infection systems expressing the envelope glycoproteins of various viruses, we find that loss of TRPM7 protects cells from infection by Lassa, LCMV, Ebola, Influenza, MERS, SARS-CoV-1, and SARS-CoV-2. TRPM7 ion channel activity is intrinsically necessary to acidify virus-laden endosomes but is expendable for several other endosomal acidification pathways. We propose a model wherein TRPM7 ion channel activity provides a countercurrent of cations from endosomal lumen to cytosol necessary to sustain the pumping of protons into these virus-laden endosomes. This study demonstrates the possibility of developing a broad-spectrum, TRPM7-targeting antiviral drug to subvert the endosomal fusion of low pH-dependent enveloped viruses.

Date: 2024
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DOI: 10.1038/s41467-024-52773-w

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