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. 2025 Aug;92(8):e70040.
doi: 10.1002/mrd.70040.

Uncovering the Role of IZUMO Family Members in Human Fertilization

Ania Antonella Manjon  1 , Gustavo Luis Verón  1 , Sergio A Garay  2 , Anahi Juarez  2 , Fernanda G E de Raffo  3 , Mónica Hebe Vazquez-Levin  1
Affiliations

Uncovering the Role of IZUMO Family Members in Human Fertilization

Ania Antonella Manjon et al. Mol Reprod Dev. 2025 Aug.

Abstract

This study investigated IZUMO1, IZUMO2, and IZUMO4 expression, localization, and participation in sperm-oocyte interaction, combining standard biochemical (Western immunoblotting and fluorescence immunocytochemistry) and functional (CPA, HZA, SPA) with computational biology approaches (bioinformatics, protein's 3D-structure modelling). Human IZUMO1, IZUMO2, and IZUMO4 transcripts were found to be testis-enriched (HPA), and expressed since puberty (MeDAS). IZUMO2 and IZUMO4 transcripts levels were lower (p < 0.05) in teratozoospermic men (GEO). Human protein forms of ~40 kDa (IZUMO1), ~23 KDa (IZUMO2) and ~25 KDa (IZUMO4) were specifically immunodetected in sperm extracts. IZUMO proteins were immunolocalized in the acrosomal region of acrosome-intact and acrosome-reacted cells. Sperm pre-incubation with anti-IZUMO antibodies resulted in lower CPA rates using anti-IZUMO4 antibodies, lower HZA rates using anti-IZUMO1, anti-IZUMO2, or anti-IZUMO4 antibodies, and lower SPA rates using anti-IZUMO1 or anti-IZUMO4 antibodies (p < 0.05). IZUMO1 and IZUMO4 were immunodetected in mouse sperm, and antibodies also blocked homologous fertilization. Protein modeling using AlphaFold identified potential antigenic regions recognized by the antibodies used in biological assays, which impaired IZUMO1-JUNO and IZUMO4-JUNO protein interactions. This is the first study that reports human IZUMO1, IZUMO2, and IZUMO4 expression/localization and involvement in gamete interaction. Findings presented enhance our understanding of the molecular interactions leading to fertilization and may contribute to male infertility diagnosis and treatment.

Keywords: HZA; IZUMO; cumulus penetration; fertilization; fusion; sperm.

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References

    1. Aydin, H., A. Sultana, S. Li, A. Thavalingam, and J. E. Lee. 2016. “Molecular Architecture of the Human Sperm IZUMO1 and Egg Juno Fertilization Complex.” Nature 534: 562–565. https://doi.org/10.1038/nature18595.
    1. Battistone, M. A., A. Alvau, A. M. Salicioni, P. E. Visconti, V. G. Da Ros, and P. S. Cuasnicu. 2014. “Evidence for the Involvement of Proline‐Rich Tyrosine Kinase 2 in Tyrosine Phosphorylation Downstream of Protein Kinase A Activation During Human Sperm Capacitation.” Molecular Human Reproduction 20: 1054–1066. https://doi.org/10.1093/molehr/gau073.
    1. Bianchi, E., B. Doe, D. Goulding, and G. J. Wright. 2014. “Juno Is the Egg Izumo Receptor and Is Essential for Mammalian Fertilization.” Nature 508: 483–487. https://doi.org/10.1038/nature13203.
    1. Bianchi, E., and G. J. Wright. 2015. “Cross‐Species Fertilization: The Hamster Egg Receptor, Juno, Binds the Human Sperm Ligand, Izumo1.” Philosophical Transactions of the Royal Society, B: Biological Sciences 370: 20140101. https://doi.org/10.1098/rstb.2014.0101.
    1. Brukman, N. G., K. P. Nakajima, C. Valansi, et al. 2023. “A Novel Function for the Sperm Adhesion Protein IZUMO1 in Cell‐Cell Fusion.” Journal of Cell Biology 222: e202207147. https://doi.org/10.1083/jcb.202207147.

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