DSSS - Origins and evolution of cell fusion: from the discovery of EFF-1 to mechanisms of egg-sperm fusion

This seminar examines cell–cell fusion as a fundamental biological process in which two or more cells merge into a single giant multinucleated cell. I define the major biological contexts of fusion, including fertilization, mating, and the development of organs such as bones, muscles and placenta, as well as pathological fusion induced by enveloped viruses, bacteria, and fungi. I outline the core membrane remodeling stages and focus on fusogens, specialized proteins that bring membranes to within nanometer distances, drive hemifusion, and promote the formation and expansion of lipidic fusion pores.

Using C. elegans, where one-third of somatic cells are invariantly programmed to fuse, I describe the forward genetic screens that uncovered the first cell-cell fusogen, EFF-1, and its paralog AFF-1. Loss-of-function phenotypes show that these fusion proteins are required to sculpt organs, control cell fates, and restrict routes of cell migration. We show that these fusogens act in a homotypic mechanism and that they are sufficient to fuse nematode, arthropod and mammalian cells that normally do not fuse. Structural studies show that EFF-1/AFF-1 are similar to class II viral fusogens from dengue, Zika, and rubella viruses, despite very low sequence conservation and mechanistic differences.

I then present HAP2/GCS1 as a distinct family of gamete fusogens required for mating and fertilization in plants and protists, which share the same structural fold with EFF-1. These findings support the Fusexin superfamily that unifies viral, somatic, and sexual fusogens under a common evolutionary framework. I discuss open evolutionary questions, including whether fusogens originated in viruses or cells, their patchy distribution across lineages, the discovery of archaeal fusexins (Fsx1) with possible roles in horizontal gene transfer, and unrelated vertebrate fusogens that appear to mediate sperm–egg fusion.