PT - JOURNAL ARTICLE AU - Ka Man Carmen Chan AU - Sungmin Son AU - Eva M. Schmid AU - Daniel A. Fletcher TI - A viral fusogen hijacks the actin cytoskeleton to drive cell-cell fusion AID - 10.1101/761502 DP - 2019 Jan 01 TA - bioRxiv PG - 761502 4099 - http://biorxiv.org/content/early/2019/09/08/761502.short 4100 - http://biorxiv.org/content/early/2019/09/08/761502.full AB - 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 the cytoplasmic domain of p14 triggers N-WASP-mediated assembly of a branched actin network, directly coupling local force generation with a short membrane-disruptive ectodomain. This work reveals that overcoming energetic barriers to cell-cell fusion does not require conformational changes of tall fusogens but can instead be driven by harnessing the host cytoskeleton.Impact Statement A viral fusogen drives cell-cell fusion by hijacking the actin machinery to directly couple actin assembly with a short fusogenic ectodomain.