ELEGANSFUSION · Mechanisms of cell fusion in eukaryotes

Membrane fusion is a universal process essential inside cells (endoplasmic) and between cells in fertilization and organ formation (exoplasmic). With the exception of SNARE-mediated endoplasmic fusion the proteins that mediate cellular fusion (fusogens) are unknown. Despite many years of research, little is known about the mechanism of cell-cell fusion. Our studies of developmental cell fusion in the nematode C. elegans have led to the discovery of the first family of eukaryotic fusogens (FF). These fusogens, EFF-1 and AFF-1, are type I membrane glycoproteins that are essential for cell fusion and can fuse cells when ectopically expressed on the membranes of C. elegans and heterologous cells.Our main goals are:(1) To determine the physicochemical mechanism of cell membrane fusion mediated by FF proteins.(2) To find the missing fusogens that act in cell fusion events across all kingdoms of life.We hypothesize that FF proteins fuse membranes by a mechanism analogous to viral or endoplasmic fusogens and that unidentified fusogens fuse cells following the same principles as FF proteins.Our specific aims are:AIM 1 Determine the mechanism of FF-mediated cell fusion: A paradigm for cell membrane fusionAIM 2 Find the sperm-egg fusion proteins (fusogens) in C. elegansAIM 3 Identify the myoblast fusogens in mammalsAIM 4 Test fusogens using functional cell fusion assays in heterologous systemsIdentifying critical domains required for FF fusion, intermediates in membrane remodeling, and atomic structures of FF proteins will advance the fundamental understanding of the mechanisms of eukaryotic cell fusion. We propose to find the Holy Grail of fertilization and mammalian myoblast fusion. We estimate that this project, if successful, will bring a breakthrough to the sperm-egg and muscle fusion fields with potential applications in basic and applied biomedical sciences.