IZUMO1 is a sperm fusogen

Mammalian sperm-egg adhesion depends on the trans-interaction between the sperm-specific type I glycoprotein IZUMO1 and its oocyte-specific GPI-anchored receptor JUNO. However, the mechanisms and proteins (fusogens) which mediate the following step of gamete fusion remain unknown. Using live imaging and content mixing assays in a heterologous system and structure-guided mutagenesis, we unveil an unexpected function for IZUMO1 in cell-to-cell fusion. We show that IZUMO1 alone is sufficient to induce fusion, and that this ability is retained in a mutant unable to bind JUNO. On the other hand, a triple mutation in exposed aromatic residues prevents this fusogenic activity without impairing JUNO interaction. Our findings suggest a second, crucial function for IZUMO1 as a unilateral mouse gamete fusogen. HighlightsO_LIIZUMO1 expression in somatic cells in culture induces cell-to-cell fusion C_LIO_LIThe fusogenic activity of IZUMO1 is unilateral C_LIO_LICell fusion is independent of the binding of IZUMO1 to JUNO C_LIO_LIIZUMO1-mediated cell merger depends on its transmembrane domain, and three solvent-exposed aromatic residues C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/478669v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1f06f47org.highwire.dtl.DTLVardef@19d5adorg.highwire.dtl.DTLVardef@1b8d6eorg.highwire.dtl.DTLVardef@e23e26_HPS_FORMAT_FIGEXP M_FIG C_FIG