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The vaccinia chondroitin sulfate binding protein drives host membrane curvature to facilitate fusion

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Cellular attachment of viruses determines their cell tropism and species specificity. For entry, vaccinia, the prototypic poxvirus, relies on four binding proteins and an eleven-protein entry fusion complex. The contribution of the individual virus binding proteins to virion binding orientation and membrane fusion is unclear. Here, we show that virus binding proteins guide side-on virion binding and promote curvature of the host membrane towards the virus fusion machinery to facilitate fusion. Using a membrane-bleb model system together with super-resolution and electron microscopy we find that side-bound vaccinia virions induce membrane invagination in the presence of low pH. Repression or deletion of individual binding proteins reveals that three of four contribute to binding orientation, amongst which the chondroitin sulphate binding protein, D8, is required for host membrane bending. Consistent with low-pH dependent macropinocytic entry of vaccinia, loss of D8 prevents virion-associated macropinosome membrane bending, disrupts fusion pore formation and infection. Our results show that viral binding proteins are active participants in successful virus membrane fusion and illustrate the importance of virus protein architecture for successful infection.


Acknowledgements: We thank B. Moss for providing the mutant viruses that were used in this study. Laura Pokorny is supported by the UCL Birkbeck MRC DTP. JJB is supported by MRC core funding to the MRC Laboratory for Molecular Cell Biology at University College London, award code (MC_U12266B). DA was funded by a Marie Skłodowska-Curie fellowship funded by the European Union (750673), RB was funded by the MRC Laboratory for Molecular Cell Biology PhD program. KEL and YM are supported by a Wellcome Trust Senior Research Fellowship (217191/Z/19/Z) to YM, PS, and TJK are supported by BBSRC grants (BB/P0098401 and BB/S017283/1) to TJK, and JM was supported by the European Research Council (649101-UbiProPox) and core funding to MRC Laboratory for Molecular Cell Biology (MC_UU_00012/7).


Glycosaminoglycans, Membrane Bending, Membrane Fusion, Poxvirus, Virus Entry, Humans, Vaccinia, Chondroitin Sulfates, Vaccinia virus, Poxviridae, Viral Proteins, Membrane Fusion, Carrier Proteins

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Wellcome Trust (101908/Z/13/Z)
Wellcome Trust (217191/Z/19/Z)