TMEM81 is an essential transmembrane protein required for male fertility in vertebrates. It functions as a critical component of a conserved trimeric sperm complex alongside IZUMO1 and SPACA6 1, forming a synapse-like assembly at the gamete membrane interface 2. This complex bridges sperm and oocyte membranes by binding to the egg receptor JUNO in mammals (or Bouncer in zebrafish), mediating sperm-egg recognition and adhesion 1. TMEM81 exhibits structural homologies with both IZUMO1 and SPACA6, enabling integrated complex formation 2. Beyond adhesion, TMEM81 functions as an essential mediator of gamete fusion through a phagocytosis-like process termed SEAL (sperm engulfment activated by IZUMO1-JUNO linkage and gamete fusion-related factors), where it facilitates dynamic membrane reorganization and actin-dependent engulfment of spermatozoa 3. Genetic evidence demonstrates that TMEM81 is indispensable for male fertility in both zebrafish and mice 1. These findings establish TMEM81 as a central player in the molecular machinery governing vertebrate fertilization, representing a potential target for understanding infertility and contraceptive development.