NLRP14 modulates the activity of E3 ubiquitin ligases during the oocyte-to-embryo transition

NLRP14 is an essential maternal factor for mammalian embryonic development. Maternal ablation of NLRP14 in mice impairs the DNA demethylation and calcium homeostasis of zygotes, leading to early embryonic arrest. However, the underlying biochemical events are still largely unknown. Here, we report that NLRP14 modulates the SKP1-CUL1-F-box (SCF) E3 ligase and the RING-type E3 ligase through two distinct mechanisms. Mechanistically, NLRP14 competitively inhibits the assembly of KDM2A-mediated SKP1-CUL1-F-box (SCF) E3 ligase and also allosterically inhibits the activity of UHRF1 via the competitive occupancy of the E2 ubiquitin ligase (UBE2) binding site of the ubiquitin-like (UBL) domain of UHRF1. Deletion of NLRP14 in mice resulted in increased protein ubiquitination levels in oocytes both during maturation and after fertilization. Along with increased proteasome levels during the oocyte-to-embryo transition, the Nlrp14 ^null oocytes exhibited an imbalance in protein homeostasis, leading to developmental arrest. Our study reveals the novel role of NLRP14 in regulating the ubiquitylation activity of E3 ligases, thereby establishing a theoretical framework for further investigation into maternal regulation of proteostasis and the pathogenesis of associated reproductive disorders.