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

• Published in: Nature communications Vol. 15; no. 1; pp. 8479 - 19
• Main Authors: Doyle, Catherine A., Busey, Gregory W., Iobst, Wesley H., Kiessling, Volker, Renken, Chloe, Doppalapudi, Hansa, Stremska, Marta E., Manjegowda, Mohan C., Arish, Mohd, Wang, Weiming, Naphade, Shardul, Kennedy, Joel, Bloyet, Louis-Marie, Thompson, Cassandra E., Rothlauf, Paul W., Stipes, Eric J., Whelan, Sean P. J., Tamm, Lukas K., Kreutzberger, Alex J. B., Sun, Jie, Desai, Bimal N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/95; 14; 14/28; 14/34; 14/35; 14/5; 14/63; 42/41; 631/326/596; 631/57/2270/1140; 631/80/2373; 9/74; Acidification; Animals; Antiviral agents; Cations; Cell fusion; Channel gating; Chlorocebus aethiops; Cytosol; Ebolavirus - metabolism; Ebolavirus - physiology; Endocytosis; Endosomes; Endosomes - metabolism; Endosomes - virology; Glycoproteins; HEK293 Cells; Humanities and Social Sciences; Humans; Hydrogen-Ion Concentration; Ion channels; Lassa virus - metabolism; Lassa virus - physiology; Lymphocytic choriomeningitis virus - physiology; Membrane fusion; multidisciplinary; Pandemics; pH effects; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protons; SARS-CoV-2 - metabolism; SARS-CoV-2 - physiology; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Transient receptor potential proteins; TRPM Cation Channels - genetics; TRPM Cation Channels - metabolism; Vesicle fusion; Viral diseases; Viral Envelope - metabolism; Viral infections; Virus Internalization; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52773-w

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. The TRPM7 channel enables endosomal acidification, which is vital for the entry of many enveloped viruses. Here, the authors show that loss of TRPM7 protects cells from various pandemic-threat viruses, pointing to a new strategy for broad-spectrum antiviral drugs.