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CEP112 coordinates translational regulation of essential fertility genes during spermiogenesis through phase separation in humans and mice

Author

Listed:
  • Xueguang Zhang

    (Sichuan University)

  • Gelin Huang

    (Sichuan University)

  • Ting Jiang

    (Sichuan University)

  • Lanlan Meng

    (Reproductive & Genetic Hospital of CITIC-Xiangya)

  • Tongtong Li

    (Sichuan University)

  • Guohui Zhang

    (Sichuan Provincial Maternity and Child Health Care Hospital)

  • Nan Wu

    (Xiamen University)

  • Xinyi Chen

    (Sichuan University)

  • Bingwang Zhao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Nana Li

    (Shandong University)

  • Sixian Wu

    (Sichuan University)

  • Junceng Guo

    (Sichuan University)

  • Rui Zheng

    (Sichuan University)

  • Zhiliang Ji

    (Xiamen University)

  • Zhigang Xu

    (Shandong University)

  • Zhenbo Wang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Dong Deng

    (Sichuan University)

  • Yueqiu Tan

    (Reproductive & Genetic Hospital of CITIC-Xiangya)

  • Wenming Xu

    (Sichuan University)

Abstract

Spermiogenesis, the complex transformation of haploid spermatids into mature spermatozoa, relies on precise spatiotemporal regulation of gene expression at the post-transcriptional level. The mechanisms underlying this critical process remain incompletely understood. Here, we identify centrosomal protein 112 (CEP112) as an essential regulator of mRNA translation during this critical developmental process. Mutations in CEP112 are discovered in oligoasthenoteratospermic patients, and Cep112-deficient male mice recapitulate key phenotypes of human asthenoteratozoospermia. CEP112 localizes to the neck and atypical centrioles of mature sperm and forms RNA granules during spermiogenesis, enriching target mRNAs such as Fsip2, Cfap61, and Cfap74. Through multi-omics analyses and the TRICK reporter assay, we demonstrate that CEP112 orchestrates the translation of target mRNAs. Co-immunoprecipitation and mass spectrometry identify CEP112’s interactions with translation-related proteins, including hnRNPA2B1, EEF1A1, and EIF4A1. In vitro, CEP112 undergoes liquid-liquid phase separation, forming condensates that recruit essential proteins and mRNAs. Moreover, variants in patient-derived CEP112 disrupt phase separation and impair translation efficiency. Our results suggest that CEP112 mediates the assembly of RNA granules through liquid-liquid phase separation to control the post-transcriptional expression of fertility-related genes. This study not only clarifies CEP112’s role in spermatogenesis but also highlights the role of phase separation in translational regulation, providing insights into male infertility and suggesting potential therapeutic targets.

Suggested Citation

  • Xueguang Zhang & Gelin Huang & Ting Jiang & Lanlan Meng & Tongtong Li & Guohui Zhang & Nan Wu & Xinyi Chen & Bingwang Zhao & Nana Li & Sixian Wu & Junceng Guo & Rui Zheng & Zhiliang Ji & Zhigang Xu & , 2024. "CEP112 coordinates translational regulation of essential fertility genes during spermiogenesis through phase separation in humans and mice," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52705-8
    DOI: 10.1038/s41467-024-52705-8
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    References listed on IDEAS

    as
    1. Marina Garcia-Jove Navarro & Shunnichi Kashida & Racha Chouaib & Sylvie Souquere & Gérard Pierron & Dominique Weil & Zoher Gueroui, 2019. "RNA is a critical element for the sizing and the composition of phase-separated RNA–protein condensates," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
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