Mechanobiology in Cell-Cell Fusion: Roles of Myosin II and Spectrin in Mechanosensing and Force Generation during Cell-Cell Fusion

Abstract

Fusion of one cell into another cell engages several biological processes including cell adhesion molecule interaction, signal transduction, cytoskeleton rearrangement and cell membrane fusion. Membrane fusion is an energy-consuming process that requires tight juxtaposition of two lipid bilayers which eventually merge into a single bilayer. Little is known about how cells overcome energy barriers to bring their membranes together for fusion. Previously, we have shown that cell-cell fusion is an asymmetric process in which an “attacking” cell drills actin-based finger-like protrusions into the “receiving” cell to promote fusion. In the studies presented here, we revealed that the receiving cell utilizes mechanosensory responses to build up cytoskeletal structures at the site of fusion (fusogenic synapse) in response to invasion by the attacking cell. MyoII acts as a mechanosensor, which directs its force-induced recruitment to the fusogenic synapse in the receiving cell, and the mechanosensory response of MyoII is amplified by cell adhesion molecule-initiated and GTPase/kinase-mediated chemical signaling. The accumulated MyoII, in turn, increases cortical tension which provides resistance on the receiving cell cortex and promotes fusion pore formation. In a similar way, the receiving cell accumulates spectrin at the fusogenic synapse. Spectrin functions as a molecular barrier which concentrates cell adhesion molecules at the fusogenic synapse. The concentrated cell adhesion molecules, in turn, induce formation of effective invasive protrusions in the attacking cell which exert pushing force into the receiving cell. We propose that the protrusive and resisting forces from two fusion partners put the fusogenic synapse under high mechanical tension, which helps to overcome the energy barriers for membrane apposition and drives cell membrane fusion.