Reovirus directly engages integrin to recruit clathrin for entry into host cells

• DOI: 10.1038/s41467-021-22380-0
• Publication Date: 2021-04-12T10:09:07Z
• Authors: Melanie Koehler; Simon J. L. Petit...; Jinsung Yang; Pavithra Aravamudhan; Xayathed Somoulay; Cristina Lo Giudice; Mégane A. Poncin; Andra C. Dumitru; Terence S. Dermody; David Alsteens
• Keywords: Science; General Physics and Astronomy; Genetics and Molecular Biology; Reoviridae; Article; Cell Line; Mice; Viral Proteins; Capsid; Cations; Animals; Point Mutation; Binding Sites; Integrin beta1; Q; Cell Membrane; Virion; General Chemistry; Clathrin; Endocytosis; N-Acetylneuraminic Acid; 3. Good health; Kinetics; General Biochemistry; Host-Pathogen Interactions; Thermodynamics; Protein Binding

AbstractReovirus infection requires the concerted action of viral and host factors to promote cell entry. After interaction of reovirus attachment protein σ1 with cell-surface carbohydrates and proteinaceous receptors, additional host factors mediate virus internalization. In particular, β1 integrin is required for endocytosis of reovirus virions following junctional adhesion molecule A (JAM-A) binding. While integrin-binding motifs in the surface-exposed region of reovirus capsid protein λ2 are thought to mediate integrin interaction, evidence for direct β1 integrin-reovirus interactions and knowledge of how integrins function to mediate reovirus entry is lacking. Here, we use single-virus force spectroscopy and confocal microscopy to discover a direct interaction between reovirus and β1 integrins. Comparison of interactions between reovirus disassembly intermediates as well as mutants and β1 integrin show that λ2 is the integrin ligand. Finally, using fluidic force microscopy, we demonstrate a functional role for β1 integrin interaction in promoting clathrin recruitment to cell-bound reovirus. Our study demonstrates a direct interaction between reovirus and β1 integrins and offers insights into the mechanism of reovirus cell entry. These results provide new perspectives for the development of efficacious antiviral therapeutics and the engineering of improved viral gene delivery and oncolytic vectors.