2. Academic Validation
  3. The E3 ubiquitin ligase adaptor KLHL8 targets ZAR1 to regulate maternal mRNA degradation in oocytes

The E3 ubiquitin ligase adaptor KLHL8 targets ZAR1 to regulate maternal mRNA degradation in oocytes

  • EMBO Rep. 2025 Sep;26(17):4364-4387. doi: 10.1038/s44319-025-00537-y.
Huizhen Fan 1,  Ruyi Liu 1,  Ran Yu 1,  Biaobang Chen 2,  Qiaoli Li 1,  Jian Mu 1,  Weijie Wang 3,  Tianyu Wu 1,  Lin He 4,  Lei Wang 5 6,  Qing Sang 7,  Zhihua Zhang 8
Affiliations

Affiliations

  • 1 Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, The State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.
  • 2 NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Fudan University, Shanghai, China.
  • 3 International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, 200030, Shanghai, China.
  • 4 Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, 200030, Shanghai, China.
  • 5 Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, The State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China. wangleiwanglei@fudan.edu.cn.
  • 6 Shanghai Academy of Natural Sciences (SANS), Fudan University, 200032, Shanghai, China. wangleiwanglei@fudan.edu.cn.
  • 7 Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, The State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China. sangqing@fudan.edu.cn.
  • 8 Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, The State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China. zhihuazhang_@fudan.edu.cn.
PMID: 40721554 DOI: 10.1038/s44319-025-00537-y
Abstract

Maternal protein homeostasis and timely degradation of maternal mRNAs are essential for meiotic cell-cycle progression and subsequent embryonic development, but the mechanisms of maternal protein degradation are poorly understood. Here, we show that KLHL8, a substrate adaptor of Cullin-RING E3 ubiquitin ligases, is highly expressed in mouse oocytes and co-localizes with mitochondria. Oocyte-specific deletion of Klhl8 causes oocyte maturation defects and female infertility. ZAR1, an RNA binding protein that is required for mitochondria-associated ribonucleoprotein domain (MARDO) dissolution, is specifically recognized and degraded by KLHL8-mediated ubiquitination. In Klhl8-deficient oocytes, ZAR1 accumulation causes abnormal MARDO and mitochondria clustering, correlating with impaired maternal mRNA decay. Supplementation with exogenous Klhl8 mRNA rescues the degradation of ZAR1 and the dissolution of the MARDO in Klhl8oo-/- oocytes. Taken together, our study shows that KLHL8 mediates the ubiquitination and degradation of ZAR1, thus regulating maternal mRNA clearance during oocyte maturation. These findings provide new insights into the roles of the ubiquitin Proteasome system during oocyte maturation and establish an interaction network between ubiquitination modification, RNA binding proteins, and maternal mRNA.

Keywords

KLHL8; Maternal mRNA Decay; Oocyte Maturation; Ubiquitination; ZAR1.

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