Deciphering the cellular and molecular mechanisms underlying mammalian sperm-egg fusion

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In the fiscal year of 2022, I published three research articles and one review article as the first author.In Tang, Lu et al. 2022 PNAS, we resolved the crystal structure of human TMEM95 by X-ray crystallography and generated monoclonal antibodies against human TMEM95 and IZUMO1. To investigate the molecular function of TMEM95, we exploited the nature that human sperm can fertilize zona-free golden hamster eggs. Using Fab fragments of the antibodies, we found that IZUMO1 Fabs ablate sperm-egg binding, in corroboration with our recent finding in mice and rats (Matsumura et al. 2022 Front Cell Dev Biol). In contrast, TMEM95 Fabs do not affect sperm-egg binding, but reduce sperm-egg fusion, suggesting that TMEM95 plays a role distinct to IZUMO1. Further, we engineered TMEM95-Fc fusion protein and discovered that the recombinant protein binds the hamster egg plasma membrane, indicating that TMEM95 has an egg receptor.In Lu et al. 2023 PNAS, we discovered that 1700029I15Rik, a type II transmembrane protein localized to the ER, regulates the biosynthesis of acrosomal membrane glycoproteins required for sperm-egg interaction. This pathway is independent from Calmegin-mediated biosynthesis of sperm plasma membrane proteins, suggesting that acrosomal and plasma membrane proteins are processed in a spatiotemporal manner.Additionally, in Lu et al. (2023) Andrology, we reported that ADAD2, in association with other RNA-binding proteins (e.g., MIWI, RNF17), regulates piRNA biogenesis in testis. Moreover, ADAD2 forms novel granules with and stabilizes RNF17 in pachytene spermatocytes.