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Published January 5, 2021 | Version Published
Journal Article Open

Evolutionarily related small viral fusogens hijack distinct but modular actin nucleation pathways to drive cell-cell fusion

Creators

  • 1. ROR icon University of California, San Francisco
  • 2. ROR icon University of California, Berkeley
  • 3. ROR icon Marine Biological Laboratory
  • 4. ROR icon University of Minnesota
  • 5. ROR icon New York University
  • 6. ROR icon California Institute of Technology
  • 7. ROR icon National Centre for Biological Sciences
  • 8. ROR icon Karolinska Institute
  • 9. ROR icon University of California, San Diego
  • 10. ROR icon Lawrence Berkeley National Laboratory
  • 11. ROR icon CZ Biohub

Abstract

Significance Most cell-cell fusogens have tall ectodomains that drive fusion by undergoing conformational changes that pull two membranes together, akin to the mechanism used by viral fusogens during enveloped virus entry. In contrast, fusion-associated small transmembrane (FAST) proteins from reovirus have short, structurally minimal, membrane-disruptive ectodomains. In this work, we show that evolutionarily distant FAST proteins from aquareovirus and orthoreovirus use different adaptor proteins to hijack host actin assembly and push two membranes together during cell-cell fusion. Despite minimal sequence similarity, the cytoplasmic tails from divergent FAST proteins can be functionally exchanged and even replaced with different actin nucleators while maintaining fusogenicity. This feature suggests a conserved biophysical strategy shared by FAST proteins that could be used by other cell-cell fusogens.

Copyright and License

© 2021. Published under the PNAS license.

Acknowledgement

We thank D.A.F. Laboratory members, especially Andrew Harris, for useful feedback and technical consultation; Conklin Laboratory at the University of California, San Francisco for providing WTC10 hiPSC line; Lavis Laboratory at Janelia for providing JF635 HaloTag ligand; Dr. Sun Hae Hong for generating the AP2-tagRFP-T hiPSC line; the UC Berkeley QB3 MacroLab for purified S. pyogenes NLS-Cas9; and Cancer Research Laboratory Flow Cytometry Facility for hiPSC sorting. This work is supported by National Institute of General Medical Sciences Grants R01GM114671 and R01GM134137 (to D.A.F.), the Chan Zuckerberg Biohub (D.A.F.), NSF Grant DBI-1548297 (to D.A.F.), and NIH Grant MIRA R35GM118149 (to D.G.D.). K.M.C.C. was funded by an NSF Graduate Research Fellowship Program fellowship. D.A.F. is a Chan Zuckerberg Biohub Investigator. A.L.A. was supported by NIH F31 Grant 1F31GM128325-01. J.M. is supported through NIH Grant F99CA253758, the New York University (NYU) Margaret and Herman Sokol Fellowship, NYU Horizon Fellowship, and German Academic Fellowship Foundation (Studienstiftung) funding. M.J. is supported by American Heart Association Postdoctoral Fellowship 18POST34000029. D.S. was supported by a Boehringer Ingelheim Fonds PhD Fellowship. J.M. and D.S. thank the Boehringer Ingelheim Fonds for generously supporting their participation in Marine Biological Laboratory Physiology Course 2019. S.S. was funded by a Life Sciences Research Foundation fellowship. We thank the Marine Biological Laboratory Physiology Course 2019 for providing an opportunity to explore initial ideas that formed the basis of this study, and we thank the Burroughs Wellcome Fund for supporting postcourse fellowships for A.L.A. and J.M. to continue the project at University of California, Berkeley.

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Additional details

Identifiers

ISSN
1091-6490

Funding

National Institute of General Medical Sciences
R01GM114671
National Institute of General Medical Sciences
R01GM134137
National Science Foundation
DBI-1548297
National Institute of General Medical Sciences
R35GM118149
National Science Foundation
GRFP
National Institute of General Medical Sciences
1F31GM128325-01
National Cancer Institute
F99CA253758
New York University
Margaret and Herman Sokol Fellowship
New York University
Horizon Fellowship
American Heart Association
18POST34000029
Boehringer Ingelheim Fonds
PhD fellowship
Boehringer Ingelheim Fonds
Travel Grant
Boehringer Ingelheim Fonds
Travel Grant
Life Sciences Research Foundation
Postdoctoral Fellowship
Burroughs Wellcome Fund
Post-Course Research
Burroughs Wellcome Fund
Post-Course Research

Dates

Available
2020-12-21
Published online

Caltech Custom Metadata

Publication Status
Published