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PreprintCited by 1Ubiquitin and proteasome pathwaysReproductive Biology and FertilityEpigenetics and DNA Methylation

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

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Deng, Dong, Liu, Sibei, Qi, Qianqian, Chi, Pengliang, Jiao, Haizhan, Yan, Li, Lu, Yuechao, Zhang, Rongrong, Li, Jinhong, Ju, Sicheng, Han, Zhuo, Zhang, Zihan, Liu, Qingting, Li, Jialu, Chen, Jing, Wang, Xiang, Li, Lei, Guo, Li, Jiao, Xue, Hu, Hongli, Jiang, Yongmei·2025·Nature Communications
DOI 10.21203/rs.3.rs-7620853/v1PMC PMC13237083

Preprint — published as 10.1038/s41467-026-71519-4 · Paper page

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Abstract

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.

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Metadata

Authors
Deng, D., Liu, S., Qi, Q., Chi, P., Jiao, H., Yan, L., Lu, Y., Zhang, R., Li, J., Ju, S., Han, Z., Zhang, Z., Liu, Q., Li, J., Chen, J., Wang, X., Li, L., Guo, L., Jiao, X., Hu, H., & Jiang, Y.
Affiliations
  • Sichuan University (CN)
  • Chinese University of Hong Kong (HK)
  • Shandong University (CN)
  • Chinese Academy of Sciences (CN)
Corresponding author
  • Deng, Dong
  • Jiao, Xue
  • Hu, Hongli
  • Jiang, Yongmei
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-10-20
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.21203/rs.3.rs-7620853/v1
PMC
PMC13237083
OpenAlex
W7152019970
Cited by
1
References
1
Citations by year
2026: 1
FWCI
2.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
E3 ubiquitin ligase, oocyte-to-embryo transition, SCF ubiquitin ligase, UHRF1, KDM2A, Skp1, ubiquitin-like domain, ubiquitination, proteostasis, maternal factors, early embryonic development, oocyte maturation, zygote, allosteric inhibition, protein complex formation
MeSH terms
Animals, Female, Humans, Oocytes, Protein Binding, Mice, Knockout, CCAAT-Enhancer-Binding Proteins, Ubiquitin-Protein Ligases, F-Box Proteins, SKP Cullin F-Box Protein Ligases, Embryonic Development, Intracellular Signaling Peptides and Proteins, Mice, Ubiquitination

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