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

Abstract

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.

A novel function for the sperm adhesion protein IZUMO1 in cell–cell fusion

“…Up to this report, GCS1 proteins were the only known fusogens involved in fertilization; these proteins are structurally and evolutionarily related to Class II fusogens from enveloped viruses and FF fusogens from nematodes ( Brukman et al, 2022 ). Together, these fusogens form a superfamily called Fusexins that have recently been identified in archaea, where they may have a primordial function in plasma membrane fusion ( Moi et al, 2022 ). However, many sexually reproducing organisms including fungi and vertebrates lack a fusexin homologue.…”

“…GCS1 structure is similar to class II viral glycoproteins (e.g., rubella and zika viruses; Fédry et al, 2017 ; Pinello et al, 2017 ; Valansi et al, 2017 ; Feng et al, 2022 ) and fusion family (FF) proteins from nematodes and other organisms ( Mohler et al, 2002 ; Sapir et al, 2007 ; Pérez-Vargas et al, 2014 ). This protein superfamily, termed Fusexins ( Valansi et al, 2017 ), are widely distributed in multiple eukaryotic and archaeal phyla ( Moi et al, 2022 ), but to date no members have been identified in vertebrates ( Brukman et al, 2022 ).…”

Malaria parasites utilize two essential plasma membrane fusogens for gamete fertilization

“…It is also possible that different HAP2 cd-loops have differential lipid binding affinities towards different target membrane lipid compositions, and it will be very interesting to determine if Pf HAP2 and Pf HAP2p have differential membrane lipid binding affinities in future studies. The recent discovery of HAP2-related Fusexin1 proteins in integrated mobile elements in archaea suggests novel mechanisms of horizontal gene transfer [ 40 ] that might help to explain the evolution of the fusexin family in eukaryotes, prokaryotes and the virome.…”

Repeat sequences limit the effectiveness of lateral gene transfer and favored the evolution of meiotic sex in early eukaryotes

“…The picture emerging from phylogenetic studies is that ancestral eukaryotes underwent a massive genome size expansion, but the precise timing of the events leading to eukaryogenesis is still a matter of debate ( 25 , 26 , 69 ). Did meiotic sex evolve after the acquisition of mitochondrial symbionts allowed eukaryotic genome size expansion ( 23 , 24 ) or were the first eukaryotes able to expand their genomes because they could already undergo syngamy (cell fusion) and reciprocal exchange of genetic material, as observed in some extant archaea ( 51 , 52 , 70 )? These archaea do not have unusually large genomes (∼4,000 genes), which suggests that mitochondrial acquisition was needed to drive the expansion in eukaryotic genome sizes, but wider sampling of archaeal genomes will throw more light on this question.…”