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Cited 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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Liu, Sibei, Qi, Qianqian, Chi, Pengliang, Jiao, Haizhan, Yan, Li, Lu, Yuechao, Zhang, Rongrong, Li, Jinhong, Ju, Sicheng, Han, Zhuo, Zhang, Zihan, Liu, Qingting, Ou, Guojin, Li, Jialu, Chen, Jing, Wang, Xiang, Li, Lei, Guo, Li, Jiao, Xue, Hu, Hongli, Jiang, Yongmei, Deng, Dong·2026·Nature Communications
DOI 10.1038/s41467-026-71519-4PMC PMC13237083

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Abstract

NLRP14 is an essential maternal factor for mammalian embryonic development. Maternal ablation of NLRP14 in mice impairs DNA demethylation and calcium homeostasis in zygotes, causing early embryonic arrest. However, the underlying biochemical events remain largely unknown. Here, we identified two binding partners (KDM2A and UHRF1) of NLRP14 and further solved structures of NLRP14-KDM2A-SKP1 and NLRP14-UHRF1. Structural analysis revealed that NLRP14 modulates the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase and the RING-type E3 ubiquitin ligase UHRF1 through two distinct mechanisms. Mechanistically, NLRP14 competitively inhibits KDM2A-mediated SCF assembly or allosterically inhibits the activity of UHRF1 by occupying the E2 ubiquitin-conjugating enzyme (UBE2D) binding site of the ubiquitin-like (UBL) domain. Deletion of NLRP14 in mice increases ubiquitination levels in oocytes during maturation and after fertilization. Collectively, our findings identify NLRP14 as a dual regulator that restrains E3 ubiquitin ligase-driven ubiquitination by limiting SCF complex assembly and attenuating UHRF1 activity. This regulatory role is required to prevent excessive protein ubiquitination and maintain proteostasis during the oocyte-to-embryo transition, thereby supporting early embryonic development. Our study uncovers maternal regulation of proteostasis in oocytes and suggests that dysregulating proteostasis is an important factor in the pathogenesis of reproductive disorders.

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Metadata

Authors
Liu, S., Qi, Q., Chi, P., Jiao, H., Yan, L., Lu, Y., Zhang, R., Li, J., Ju, S., Han, Z., Zhang, Z., Liu, Q., Ou, G., Li, J., Chen, J., Wang, X., Li, L., Guo, L., Jiao, X., Hu, H., Jiang, Y., & Deng, D.
Affiliations
  • Sichuan University (CN)
  • Chinese University of Hong Kong (HK)
  • Shandong University (CN)
  • Chinese Academy of Sciences (CN)
Corresponding author
  • Jiao, Xue
  • Hu, Hongli
  • Jiang, Yongmei
  • Deng, Dong
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2026-04-08
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-026-71519-4
PMC
PMC13237083
OpenAlex
W7152019970
Cited by
1
References
2
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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