UC Berkeley–UC San Francisco Graduate Group in Bioengineering, Berkeley, United States; Department of Bioengineering & Biophysics Graduate Group, University of California, Berkeley, Berkeley, United States
Sungmin Son
Department of Bioengineering & Biophysics Graduate Group, University of California, Berkeley, Berkeley, United States
Eva M Schmid
Department of Bioengineering & Biophysics Graduate Group, University of California, Berkeley, Berkeley, United States
UC Berkeley–UC San Francisco Graduate Group in Bioengineering, Berkeley, United States; Department of Bioengineering & Biophysics Graduate Group, University of California, Berkeley, Berkeley, United States; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, United States; Chan Zuckerberg Biohub, San Francisco, United States
Cell-cell fusion, which is essential for tissue development and used by some viruses to form pathological syncytia, is typically driven by fusogenic membrane proteins with tall (>10 nm) ectodomains that undergo conformational changes to bring apposing membranes in close contact prior to fusion. Here we report that a viral fusogen with a short (<2 nm) ectodomain, the reptilian orthoreovirus p14, accomplishes the same task by hijacking the actin cytoskeleton. We show that phosphorylation of the cytoplasmic domain of p14 triggers N-WASP-mediated assembly of a branched actin network. Using p14 mutants, we demonstrate that fusion is abrogated when binding of an adaptor protein is prevented and that direct coupling of the fusogenic ectodomain to branched actin assembly is sufficient to drive cell-cell fusion. This work reveals how the actin cytoskeleton can be harnessed to overcome energetic barriers to cell-cell fusion.
