Furin‐Mediated Cleavage of Zona Pellucida Proteins Is Essential for Oocyte Development

Zona pellucida (ZP) proteins, essential for oocyte development, undergo posttranslational regulation through furin-mediated cleavage. Nevertheless, our understanding of the functional significance of furin-mediated cleavage of ZP proteins in female reproduction remains limited. Here, using mouse models with disrupted furin cleavage sites in ZP1, ZP2, and ZP3, we found that loss of the furin site in ZP2 caused female infertility associated with empty follicle syndrome (EFS), manifested by the failure to retrieve oocytes after ovarian hyperstimulation. In contrast, female mice carrying cleavage-resistant variants at the furin sites of ZP1 and ZP3 exhibited defective ZP in a subset of oocytes, leading to reduced fecundity. Mechanistically, disruption of the furin cleavage site in ZP2 impaired the transmembrane transport of the non-cleaved ZP2 protein and subsequently reduced the levels of SNARE proteins, ultimately triggering oocyte apoptosis through activation of the p53 and PI3K signaling pathways. Collectively, we uncovered the essential role of furin-mediated cleavage of ZP proteins in female fertility and provided new mechanistic insights into the pathogenesis of EFS. These findings open new avenues for investigating the contribution of posttranslational modifications to female reproduction and for developing potential therapeutic strategies to treat female infertility.