Discovery of archaeal fusexins homologous to eukaryotic HAP2/GCS1 gamete fusion proteins

Sexual reproduction consists of genome reduction by meiosis and subsequent gamete fusion. The presence of genes homologous to eukaryotic meiotic genes in archaea and bacteria suggests that DNA repair mechanisms evolved towards meiotic recombination. However, fusogenic proteins resembling those found in gamete fusion in eukaryotes have so far not been found in prokaryotes. Here, we identify archaeal proteins that are homologs of fusexins, a superfamily of fusogens that mediate eukaryotic gamete and somatic cell fusion, as well as virus entry. The crystal structure of a trimeric archaeal fusexin (Fusexin1 or Fsx1) reveals an archetypical fusexin architecture with unique features such as a six-helix bundle and an additional globular domain. Ectopically expressed Fusexin1 can fuse mammalian cells, and this process involves the additional globular domain and a conserved fusion loop. Furthermore, archaeal fusexin genes are found within integrated mobile elements, suggesting potential roles in cell-cell fusion and gene exchange in archaea, as well as different scenarios for the evolutionary history of fusexins. Sexual reproduction in eukaryotes involves gamete fusion, mediated by fusogenic proteins. Here, the authors identify fusogenic protein homologs encoded within mobile genetic elements in archaeal genomes, solve the crystal structure of one of the proteins, and show that its ectopic expression can fuse mammalian cells, suggesting potential roles in cell-cell fusion and gene exchange.