Role of membrane proximal actin regulators in SARS-CoV-2 spike-induced cell-cell fusion

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein has the ability to induce multinucleated syncytia via cell-cell fusion, which is thought to be related to the pathogenesis of the coronavirus disease 2019 (COVID-19). However, the mechanism by which spike protein regulates cell fusion remains unclear. Given the close correlation between cell-cell fusion and membrane protrusions, we investigated the role of membrane-proximal actin regulators in spike-induced cell fusion. We found that while Rac-Arp2/3 dependent branched actin polymerization is required for spike-mediated cell fusion, RhoA dependent actomyosin contractility has an inhibitory effect on fusion. In addition, plasma membrane tension regulated by membrane-cortex attachment plays a negative role in spike-dependent cell fusion. Furthermore, we identified several BAR proteins, which couple membrane curvature with actin dynamics, involved in spike-induced syncytia formation. Our study suggests that these actin regulators could be promising targets for inhibiting SARS-CoV-2 spike protein-induced syncytia formation.