Department of Pharmacology, University of Virginia, Charlottesville, VA, USA.
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
Nat Commun. 2024 Oct 1;15(1):8479. 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.
大多数被归类为大流行威胁的病毒都是包膜病毒，它们通过受体介导的内吞作用进入细胞，并利用内体酸化来激活它们的融合机制。在这里，我们报告低 pH 要求的病毒的内体融合高度依赖于 TRPM7，这是一种广泛表达的 TRP 通道，位于质膜和细胞内囊泡上。使用几种表达各种病毒包膜糖蛋白的病毒感染系统，我们发现 TRPM7 的缺失可保护细胞免受拉萨热、LCMV、埃博拉、流感、MERS、SARS-CoV-1 和 SARS-CoV-2 的感染。TRPM7 离子通道活性对于酸化载病毒的内体是内在必需的，但对于其他几种内体酸化途径是可有可无的。我们提出了一个模型，其中 TRPM7 离子通道活性提供了从内体腔到细胞质的阳离子的逆流，这对于将质子泵入这些载病毒的内体是必要的。这项研究表明，有可能开发一种广谱的、针对 TRPM7 的抗病毒药物，以颠覆低 pH 依赖性包膜病毒的内体融合。
