1. Endosomal fusion of pH-dependent enveloped viruses requires ion channel TRPM7.
- Author
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Doyle CA, Busey GW, Iobst WH, Kiessling V, Renken C, Doppalapudi H, Stremska ME, Manjegowda MC, Arish M, Wang W, Naphade S, Kennedy J, Bloyet LM, Thompson CE, Rothlauf PW, Stipes EJ, Whelan SPJ, Tamm LK, Kreutzberger AJB, Sun J, and Desai BN
- Subjects
- Hydrogen-Ion Concentration, Humans, Animals, HEK293 Cells, SARS-CoV-2 physiology, SARS-CoV-2 metabolism, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases genetics, Ebolavirus physiology, Ebolavirus metabolism, Lymphocytic choriomeningitis virus physiology, Chlorocebus aethiops, Viral Envelope metabolism, Lassa virus metabolism, Lassa virus physiology, TRPM Cation Channels metabolism, TRPM Cation Channels genetics, Endosomes metabolism, Endosomes virology, Virus Internalization
- 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., (© 2024. The Author(s).)
- Published
- 2024
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